22-28719462-C-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_007194.4(CHEK2):c.616G>A(p.Val206Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000565 in 1,594,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000049 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
8
11
Clinical Significance
Conservation
PhyloP100: 4.05
Genes affected
CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.3430393).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.616G>A | p.Val206Ile | missense_variant | 5/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.616G>A | p.Val206Ile | missense_variant | 5/15 | 1 | NM_007194.4 | ENSP00000385747.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152034Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000485 AC: 7AN: 1442012Hom.: 0 Cov.: 27 AF XY: 0.00000419 AC XY: 3AN XY: 716466
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152034Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74274
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 09, 2023 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 206 of the CHEK2 protein (p.Val206Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 232611). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 19, 2024 | The p.V206I variant (also known as c.616G>A), located in coding exon 4 of the CHEK2 gene, results from a G to A substitution at nucleotide position 616. The valine at codon 206 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T;.;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;.;D;D;D;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;L;L;.;L;.;L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;.;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T;T;.;T;T;T
Sift4G
Benign
T;T;T;T;T;.;T;T;T
Polyphen
P;P;P;P;P;P;D;P;.
Vest4
MutPred
Loss of catalytic residue at V206 (P = 0.0099);Loss of catalytic residue at V206 (P = 0.0099);Loss of catalytic residue at V206 (P = 0.0099);Loss of catalytic residue at V206 (P = 0.0099);.;Loss of catalytic residue at V206 (P = 0.0099);.;Loss of catalytic residue at V206 (P = 0.0099);.;
MVP
MPC
0.12
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at