rs8135424

chr22-28689804-G-A

Variant summary

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

The NM_007194.4(CHEK2):c.1462-589C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,120 control chromosomes in the GnomAD database, including 1,618 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 0.14 (1618 hom., cov: 32)
• Consequence: CHEK2 NM_007194.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4	c.1462-589C>T		intron_variant		ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6	c.1462-589C>T		intron_variant		1	NM_007194.4	P2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20612 AN: 152002 Hom.: 1613 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.0988

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.136 AC: 20630 AN: 152120 Hom.: 1618 Cov.: 32 AF XY: 0.136 AC XY: 10078 AN XY: 74364

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.0949

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.0990

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.103

Alfa AF: 0.130 Hom.: 459

Bravo AF: 0.130

Asia WGS AF: 0.0720 AC: 254 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	2.3
Dann	Benign	0.74

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: rs8135424; hg19: chr22-29085792;