rs1064793511

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_007194.4(CHEK2):​c.1415A>T​(p.Lys472Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K472E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CHEK2
NM_007194.4 missense

Scores

6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.89
Variant links:
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 Uncertain_significance. Variant got 3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_007194.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31543154).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHEK2NM_007194.4 linkuse as main transcriptc.1415A>T p.Lys472Met missense_variant 13/15 ENST00000404276.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHEK2ENST00000404276.6 linkuse as main transcriptc.1415A>T p.Lys472Met missense_variant 13/151 NM_007194.4 P2O96017-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.012
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.26
T;.;T;.;T;.;T;.;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.79
.;T;.;D;.;D;D;D;.
M_CAP
Benign
0.061
D
MetaRNN
Benign
0.32
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
1.7
L;.;L;.;L;.;L;.;.
MutationTaster
Benign
0.95
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-2.4
N;N;N;.;N;D;.;N;N
REVEL
Benign
0.19
Sift
Benign
0.056
T;T;T;.;T;T;.;D;T
Sift4G
Uncertain
0.033
D;D;D;.;D;D;.;D;D
Polyphen
0.32
B;B;B;.;B;P;B;B;B
Vest4
0.50
MutPred
0.40
Gain of catalytic residue at V468 (P = 0.0244);.;Gain of catalytic residue at V468 (P = 0.0244);.;Gain of catalytic residue at V468 (P = 0.0244);.;Gain of catalytic residue at V468 (P = 0.0244);.;.;
MVP
0.78
MPC
0.032
ClinPred
0.71
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.26
gMVP
0.42

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-29090066; API