chr22-28703766-T-C

Position:

• chr22-28703766-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000404276.6(CHEK2):​c.847-200A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 151,914 control chromosomes in the GnomAD database, including 11,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.36 (11682 hom., cov: 31)
• Consequence: CHEK2 ENST00000404276.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0160

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-28703766-T-C is Benign according to our data. Variant chr22-28703766-T-C is described in ClinVar as [Benign]. Clinvar id is 1292660.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHEK2	NM_007194.4	c.847-200A>G		intron_variant		ENST00000404276.6	NP_009125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6	c.847-200A>G		intron_variant		1	NM_007194.4	ENSP00000385747	P2

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54529 AN: 151796 Hom.: 11686 Cov.: 31

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.366

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

GnomAD4 genome AF: 0.359 AC: 54513 AN: 151914 Hom.: 11682 Cov.: 31 AF XY: 0.358 AC XY: 26582 AN XY: 74214

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.482

Gnomad4 OTH AF: 0.363

Alfa AF: 0.446 Hom.: 3730

Bravo AF: 0.330

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.8
DANN	Benign	0.75

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: rs2267130; hg19: chr22-29099754;