22-28695868-A-AG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2_SupportingPP5_Moderate

The ENST00000404276(CHEK2):c.1100_1101insC(p.Asp368Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

CHEK2
ENST00000404276 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.67

Links

CHEK2 (HGNC:16627):

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant; Number of alleles below threshold, Median coverage is 32.

PP5

Variant 22:28695868-A>AG is Pathogenic according to our data. Variant chr22-28695868-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 2452083. Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHEK2	NM_007194.4 linkuse as main transcript	c.1100_1101insC	p.Asp368Ter	frameshift_variant	11/15	ENST00000404276.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHEK2	ENST00000404276.6 linkuse as main transcript	c.1100_1101insC	p.Asp368Ter	frameshift_variant	11/15	1	NM_007194.4	P2	O96017-1

Frequencies

GnomAD3 genomes

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2023

The c.1100dupC pathogenic mutation, located in coding exon 10 of the CHEK2 gene, results from a duplication of C at nucleotide position 1100, causing a translational frameshift with a predicted alternate stop codon (p.D368*). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.