15-93020014-C-T

Position:

• chr15-93020014-C-T

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.4909C>T​(p.Arg1637*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.80

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 15-93020014-C-T is Pathogenic according to our data. Variant chr15-93020014-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 218398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-93020014-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4	c.4909C>T	p.Arg1637*	stop_gained, splice_region_variant	38/39	ENST00000394196.9	NP_001262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.4909C>T	p.Arg1637*	stop_gained, splice_region_variant	38/39	5	NM_001271.4	ENSP00000377747.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jul 31, 2020	This nonsense variant found in exon 38 of 39 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a de novo change in an individual affected with childhood-onset epileptic encephalopathy (PMID: 25783594) as well as in individuals with intellectual disability and/or autism spectrum disorders (PMID: 25363768, 25418537, 28191890, 31332282). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4909C>T (p.Arg1637Ter) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2023	This sequence change creates a premature translational stop signal (p.Arg1637*) 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 childhood-onset epileptic encephalopathy (PMID: 25783594). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 218398). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Splice site region, Nonsense variant c.4909C>T in Exon 38 of the CHD2 gene that results in the amino acid substitution p.Arg1637* was identified. The observed variant has a minor allele frequency of 0.000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 218398 as of 2023-01-07). This nonsense variant found in exon 38 of 39 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a de novo change in an individual affected with childhood-onset epileptic encephalopathy (Galizia, Elizabeth C et al., 2015) as well as in individuals with intellectual disability and/or autism spectrum disorders (Kosmicki, Jack A et al., 2017; Du, Yaoqiang et al., 2020). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CHD2: PS2:Very Strong, PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25783594, 25418537, 25363768, 28191890, 26677509, 31332282, 28714951, 31981491, 31785789, 34859793) -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Sep 27, 2022

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2017

The p.R1637* pathogenic mutation (also known as c.4909C>T), located in coding exon 37 of the CHD2 gene, results from a C to T substitution at nucleotide position 4909. This changes the amino acid from an arginine to a stop codon within coding exon 37. In a cohort of individuals with autism spectrum disorders and an absence of a family history, this mutation was identified in a 9-year-old individual with no history of seizures (O'Roak BJ et al. Nat Commun, 2014 Nov;5:5595). In another study, this mutation occurred de novo in an individual whose phenotype evolved from early-onset absence epilepsy to idiopathic photosensitive occipital lobe epilepsy (Galizia EC et al. Brain, 2015 May;138:1198-207). In addition to the clinical data presented in the literature, 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. -

CHD2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

The CHD2 c.4909C>T variant is predicted to result in premature protein termination (p.Arg1637*). This variant has been reported as de novo in a patient with idiopathic photosensitive occipital epilepsy and in several patients with autism spectrum disorder (Galizia et al. 2015. PubMed ID: 25783594; Table S2, Iossifov et al. 2014. PubMed ID: 25363768; Table S1, O'Roak et al. 2014. PubMed ID: 25418537; Table S1, Kosmicki et al. 2017. PubMed ID: 28191890). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in CHD2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.72
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs864309547; hg19: chr15-93563244;