15-92997085-GA-GAA

Position:

• chr15-92997085-GA-GAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_001271.4(CHD2):​c.3734dupA variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,369,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (0 hom.)
• Consequence: CHD2 NM_001271.4 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.89

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]

CHD2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 15-92997085-G-GA is Pathogenic according to our data. Variant chr15-92997085-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 803141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 4436 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4	c.3734dupA		splice_donor_variant, intron_variant		ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.3734dupA		splice_donor_variant, intron_variant		5	NM_001271.4	ENSP00000377747.4
CHD2	ENST00000637789.1	n.*309dupA		splice_donor_variant, intron_variant		5		ENSP00000489767.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 147966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00363 AC: 4436 AN: 1221856 Hom.: 0 Cov.: 32 AF XY: 0.00375 AC XY: 2271 AN XY: 606408

Gnomad4 AFR exome AF: 0.00564

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.00647

Gnomad4 EAS exome AF: 0.00437

Gnomad4 SAS exome AF: 0.00593

Gnomad4 FIN exome AF: 0.00441

Gnomad4 NFE exome AF: 0.00302

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 147966 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71978

Gnomad4 AFR AF: 0.0000248

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000106

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 803141). This premature translational stop signal has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 31677157). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Tyr1246Ilefs*13) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -

CHD2-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The CHD2 c.3734dupA variant is predicted to result in a frameshift and premature protein termination (p.Tyr1246Ilefs*13). This variant was reported to occur de novo in an individual with an epilepsy phenotype (Supplemental Table 1, Chen et al 2019. PubMed ID: 31677157). This variant is reported in 1.9% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, however this variant is within a region of sequence complexity and thus population-based frequency reports based on short read next-generation sequencing technology are likely inaccurate. However, frameshift variants in CHD2 are expected to be pathogenic and therefore we interpret this variant as likely 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: rs752940775; hg19: chr15-93540315;