rs2017309

chr22-28735438-T-Achr22-28735438-T-Cchr22-28735438-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007194.4(CHEK2):c.-6-711A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 151,924 control chromosomes in the GnomAD database, including 4,249 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4249 hom., cov: 32)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.147

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.-6-711A>T		intron_variant		ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.-6-711A>T		intron_variant		1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34686 AN: 151806 Hom.: 4243 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.257

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

GnomAD4 genome AF: 0.229 AC: 34726 AN: 151924 Hom.: 4249 Cov.: 32 AF XY: 0.233 AC XY: 17279 AN XY: 74242

Gnomad4 AFR AF: 0.256

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.338

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.257

Alfa AF: 0.197 Hom.: 377

Bravo AF: 0.243

Asia WGS AF: 0.361 AC: 1254 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.8
Dann	Benign	0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2017309; hg19: chr22-29131426; COSMIC: COSV60415885; COSMIC: COSV60415885;