rs738722

chr22-28734024-T-Cchr22-28734024-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_007194.4(CHEK2):c.319+379A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 151,918 control chromosomes in the GnomAD database, including 35,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency: Genomes: 𝑓 0.68 (35599 hom., cov: 31)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.634

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 22-28734024-T-C is Benign according to our data. Variant chr22-28734024-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.319+379A>G		intron_variant		ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.319+379A>G		intron_variant		1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.678 AC: 102989 AN: 151800 Hom.: 35583 Cov.: 31

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.839

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.700

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.678 AC: 103048 AN: 151918 Hom.: 35599 Cov.: 31 AF XY: 0.682 AC XY: 50652 AN XY: 74240

Gnomad4 AFR AF: 0.561

Gnomad4 AMR AF: 0.652

Gnomad4 ASJ AF: 0.823

Gnomad4 EAS AF: 0.786

Gnomad4 SAS AF: 0.839

Gnomad4 FIN AF: 0.734

Gnomad4 NFE AF: 0.719

Gnomad4 OTH AF: 0.696

Alfa AF: 0.725 Hom.: 91814

Bravo AF: 0.665

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
Cadd	Benign	0.68
Dann	Benign	0.61

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: rs738722; hg19: chr22-29130012; COSMIC: COSV60415870; COSMIC: COSV60415870;