rs752940775

Positions:

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

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.Lys1245fs) 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]

CHD2 (HGNC:):

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/exons	MANE	Protein	UniProt
CHD2	NM_001271.4	c.3734delA	p.Lys1245fs	frameshift_variant, splice_region_variant	29/39	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.3734delA	p.Lys1245fs	frameshift_variant, splice_region_variant	29/39	5	NM_001271.4	ENSP00000377747.4
CHD2	ENST00000637789.1	n.*309delA		splice_region_variant, non_coding_transcript_exon_variant	6/9	5		ENSP00000489767.1
CHD2	ENST00000637789.1	n.*309delA		3_prime_UTR_variant	6/9	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

Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	Jun 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 425077). This premature translational stop signal has been observed in individual(s) with clinical features of CHD2-related conditions (PMID: 25783594). 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.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). -

not provided Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CHD2: BS1, BS2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2017	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2020

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;