rs1555444702

chr15-92998550-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.3937C>T(p.Arg1313Ter) variant causes a stop gained 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.90

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 15-92998550-C-T is Pathogenic according to our data. Variant chr15-92998550-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 521625.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.3937C>T	p.Arg1313Ter	stop_gained	31/39	ENST00000394196.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.3937C>T	p.Arg1313Ter	stop_gained	31/39	5	NM_001271.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change creates a premature translational stop signal (p.Arg1313*) 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 clinical features of developmental and epileptic encephalopathy (PMID: 31618753). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 521625). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This nonsense variant found in exon 31 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 reported as a de novo change in an individual with childhood-onset epileptic encephalopathy (PMID: 31618753). Loss-of-function variation in CHD2 is an established mechanism of disease (PMID: 23708187, 24207121, 28492532). The c.3937C>T (p.Arg1313Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.3937C>T (p.Arg1313Ter) variant is classified as a Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.3937C>T (p.R1313*) alteration, located in exon 31 (coding exon 30) of the CHD2 gene, consists of a C to T substitution at nucleotide position 3937. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1313. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in a girl with epilepsy and moderate intellectual disability (Ziats, 2020; Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31618753, 23708187, 24207121, 34713950) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.97
GERP RS		3.4
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: rs1555444702; hg19: chr15-93541780;