chr22-28734590-G-C

Position:

• chr22-28734590-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007194.4(CHEK2):​c.132C>G​(p.Ser44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S44T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHEK2 NM_007194.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.696

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18875828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.132C>G	p.Ser44Arg	missense_variant	2/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.132C>G	p.Ser44Arg	missense_variant	2/15	1	NM_007194.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;T;T;.;T;.;.;.;.;T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.82	.;T;.;.;T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.8	L;L;L;L;L;L;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;N;N;N;N;.;N;N;N;N;D;.;.
REVEL	Benign	0.079
Sift	Benign	0.051	T;T;T;T;D;.;D;T;D;D;D;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;.;D;D;D;D;D;.;.
Polyphen		0.43	B;P;B;B;P;B;P;P;.;.;.;.;.
Vest4		0.39
MutPred		0.38		Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);Loss of phosphorylation at S44 (P = 0.0018);
MVP		0.97
MPC		0.033
ClinPred		0.33	T
GERP RS		4.2
Varity_R		0.061
gMVP		0.30

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: chr22-29130578;