rs752940775

Variant names:

• chr15-92997085-GA-G
• rs752940775
• ENST00000394196.9:c.3723delA

Your query was ambiguous. Multiple possible variants found:

• chr15-92997085-GA-G
• chr15-92997085-GA-GAA
• chr15-92997085-GA-GAAA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_001271.4(CHD2):​c.3734delA​(p.Lys1245AsnfsTer4) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,462,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: CHD2 NM_001271.4 frameshift, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 B:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High AC in GnomAdExome4 at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD2	NM_001271.4	c.3734delA	p.Lys1245AsnfsTer4	frameshift_variant, splice_region_variant	Exon 29 of 39	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.3723delA	p.Glu1242AsnfsTer4	frameshift_variant	Exon 29 of 39	5	NM_001271.4	ENSP00000377747.4
CHD2	ENST00000637789.1	n.*298delA		non_coding_transcript_exon_variant	Exon 6 of 9	5		ENSP00000489767.1
CHD2	ENST00000637789.1	n.*298delA		3_prime_UTR_variant	Exon 6 of 9	5		ENSP00000489767.1

Frequencies

GnomAD3 genomes AF: 0.00000676 AC: 1 AN: 147986 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000875 AC: 115 AN: 1314122 Hom.: 0 Cov.: 32 AF XY: 0.0000797 AC XY: 52 AN XY: 652612

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000789

Gnomad4 ASJ exome AF: 0.000177

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.000235

Gnomad4 FIN exome AF: 0.0000834

Gnomad4 NFE exome AF: 0.0000454

Gnomad4 OTH exome AF: 0.000186

GnomAD4 genome AF: 0.00000676 AC: 1 AN: 147986 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71982

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000105

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00111 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Pathogenic:2

Jan 17, 2025

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.Lys1245Asnfs*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). 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 premature translational stop signal has been observed in individual(s) with clinical features of CHD2-related conditions (PMID: 25783594). ClinVar contains an entry for this variant (Variation ID: 425077). For these reasons, this variant has been classified as Pathogenic. -

Jun 27, 2022

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Benign:1

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHD2: BS1, BS2 -

Oct 26, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3734delA variant in the CHD2 gene has been reported previously in association with autism (Bi et al., 2012). The c.3734delA variant was also reported using alternate nomenclature (c.3725delA) in an individual with eyelid myoclonia with absences, autism, nephrolithiasis, migraines, and scoliosis (Galizia et al., 2015). The c.3734delA variant causes a frameshift starting with codon Lysine 1245, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Lys1245AsnfsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3734delA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.3734delA as a pathogenic variant that is consistent with the reported developmental delay, autism, intellectual disability, ataxia, and abnormal EEG findings in this individual. -

History of neurodevelopmental disorder Pathogenic:1

Oct 08, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3734delA pathogenic mutation, located in coding exon 28 of the CHD2 gene, results from a deletion of one nucleotide at nucleotide position 3734, causing a translational frameshift with a predicted alternate stop codon (p.K1245Nfs*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: rs752940775; hg19: chr15-93540315;