NM_001271.4:c.3787dupG

Variant names:

• chr15-92997299-T-TG
• rs869312877
• NM_001271.4:c.3787dupG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001271.4(CHD2):​c.3787dupG​(p.Val1263GlyfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD2 NM_001271.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.54

Genes affected

CHD2 (HGNC:1917): (chromodomain helicase DNA binding protein 2) The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-92997299-T-TG is Pathogenic according to our data. Variant chr15-92997299-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 224140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD2	NM_001271.4	c.3787dupG	p.Val1263GlyfsTer4	frameshift_variant	Exon 30 of 39	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.3787dupG	p.Val1263GlyfsTer4	frameshift_variant	Exon 30 of 39	5	NM_001271.4	ENSP00000377747.4
CHD2	ENST00000637789.1	n.*362dupG		non_coding_transcript_exon_variant	Exon 7 of 9	5		ENSP00000489767.1
CHD2	ENST00000637789.1	n.*362dupG		3_prime_UTR_variant	Exon 7 of 9	5		ENSP00000489767.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Pathogenic:2

Dec 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val1263Glyfs*4) in the CHD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHD2 are known to be pathogenic (PMID: 23708187, 24207121). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of childhood-onset epileptic encephalopathy (PMID: 28554332, 31273778). ClinVar contains an entry for this variant (Variation ID: 224140). For these reasons, this variant has been classified as Pathogenic. -

Aug 07, 2015

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Jun 29, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3787dupG pathogenic mutation, located in coding exon 29 of the CHD2 gene, results from a duplication of G at nucleotide position 3787, causing a translational frameshift with a predicted alternate stop codon (p.V1263Gfs*4). 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs869312877; hg19: chr15-93540529;