rs757530141

Positions:

• chr22-28734697-C-A
• chr22-28734697-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007194.4(CHEK2):​c.25G>T​(p.Ala9Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.57

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022809297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.25G>T	p.Ala9Ser	missense_variant	2/15	ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.25G>T	p.Ala9Ser	missense_variant	2/15	1	NM_007194.4	ENSP00000385747.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245996 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.10
DANN	Benign	0.90
DEOGEN2	Benign	0.080	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.58	.;T;.;.;T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.023	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	-0.26	N;N;N;N;N;N;N;N;.;.;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.13	N;N;N;N;N;.;N;N;N;N;N;.;.
REVEL	Benign	0.073
Sift	Benign	0.47	T;T;T;T;T;.;D;T;T;T;T;.;.
Sift4G	Benign	0.50	T;T;T;T;T;.;T;T;T;T;T;.;.
Polyphen		0.0	B;B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.091
MutPred		0.094		Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);Gain of phosphorylation at A9 (P = 0.0153);
MVP		0.62
MPC		0.019
ClinPred		0.018	T
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.022
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs757530141; hg19: chr22-29130685;