22-28734603-C-A

Position:

• chr22-28734603-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007194.4(CHEK2):​c.119G>T​(p.Ser40Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. S40G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3027746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.119G>T	p.Ser40Ile	missense_variant	2/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.119G>T	p.Ser40Ile	missense_variant	2/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Benign	0.025
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	.;T;.;.;T;T;T;.;T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N;N;N;N;N;.;N;N;N;N;D;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;D;D;D;D;.;D;D;D;D;D;.;.
Sift4G	Benign	0.17	T;T;T;T;T;.;D;T;D;D;D;.;.
Polyphen		0.81	P;P;P;P;P;P;P;P;.;.;.;.;.
Vest4		0.53
MutPred		0.32		Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);Loss of phosphorylation at S40 (P = 0.0017);
MVP		0.97
MPC		0.11
ClinPred		0.78	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.57

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: chr22-29130591;