VCV000855582.9 - ClinVar - NCBI (2024)

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Identifiers

NM_007194.4(CHEK2):c.1334A>G (p.Tyr445Cys)

Variation ID: 855582 Accession: VCV000855582.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.1 22: 28695168 (GRCh38) [ NCBI UCSC ] 22: 29091156 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 15, 2020	Feb 20, 2024	Aug 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_007194.4:c.1334A>G MANESelect Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009125.1:p.Tyr445Cys	missense
NM_001005735.2:c.1463A>G	NP_001005735.1:p.Tyr488Cys	missense
NM_001257387.2:c.671A>G	NP_001244316.1:p.Tyr224Cys	missense
NM_001349956.2:c.1133A>G	NP_001336885.1:p.Tyr378Cys	missense
NM_145862.2:c.1247A>G	NP_665861.1:p.Tyr416Cys	missense
NC_000022.11:g.28695168T>C
NC_000022.10:g.29091156T>C
NG_008150.2:g.51699A>G
LRG_302:g.51699A>G
LRG_302t1:c.1334A>G	LRG_302p1:p.Tyr445Cys

... more HGVS ... less HGVS

Protein change

Y416C, Y488C, Y378C, Y224C, Y445C

Other names

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Canonical SPDI

NC_000022.11:28695167:T:C

Functional
consequence Help

The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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Global minor allele
frequency (GMAF) Help

The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

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Allele frequency Help

The frequency of the allele represented by this VCV record.

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Links

dbSNP: rs778246892

VarSome

The p.Y445C variant (also known as c.1334A>G), located in coding exon 11 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1334. The tyrosine at codon 445 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 855582). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 445 of the CHEK2 protein (p.Tyr445Cys).