rs1555445685

chr15-93014769-ACT-A

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.4771_4772del(p.Leu1591AspfsTer32) variant causes a frameshift change. 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: 4.43

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 15-93014769-ACT-A is Pathogenic according to our data. Variant chr15-93014769-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 521424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD2	NM_001271.4	c.4771_4772del	p.Leu1591AspfsTer32	frameshift_variant	37/39	ENST00000394196.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.4771_4772del	p.Leu1591AspfsTer32	frameshift_variant	37/39	5	NM_001271.4	P1
CHD2	ENST00000626874.2	c.4771_4772del	p.Leu1591AspfsTer32	frameshift_variant	37/38	1
CHD2	ENST00000625662.3	c.*942_*943del		3_prime_UTR_variant, NMD_transcript_variant	33/35	5
CHD2	ENST00000627460.1	c.49-42_49-41del		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2016

- -

CHD2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2022

The CHD2 c.4771_4772delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu1591Aspfs*32). This variant was reported to have occurred de novo in two individuals with developmental and epileptic encephalopathy (described as c.4767_4768delCT p.(Leu1591Aspfs), Strauss et al. 2018. PubMed ID: 28726809; De Maria et al. 2021. PubMed ID: 34713950). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in CHD2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Developmental and epileptic encephalopathy 94 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2019

This variant has been observed in individual(s) with epileptic encephalopathy (PMID: 28726809). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 521424). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu1591Aspfs*32) 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). For these reasons, this variant has been classified as Pathogenic. -

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: rs1555445685; hg19: chr15-93557999;