15-92901296-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001271.4(CHD2):c.59C>G(p.Ser20Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S20L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.45

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CHD2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD2	NM_001271.4	c.59C>G	p.Ser20Trp	missense_variant	2/39	ENST00000394196.9
CHD2	NM_001042572.3	c.59C>G	p.Ser20Trp	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.59C>G	p.Ser20Trp	missense_variant	2/39	5	NM_001271.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 31

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445708 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 720026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2017

A variant of uncertain significance has been identified in the CHD2 gene. The S20W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S20W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S20W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Developmental and epileptic encephalopathy 94 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 09, 2023

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 20 of the CHD2 protein (p.Ser20Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 393128). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHD2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	28
Dann	Benign	0.97
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D;D;T;T;D;D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
Sift4G	Uncertain	0.0080	D;D;D;.;.;D;D
Polyphen		1.0	.;D;D;.;.;.;.
Vest4		0.55, 0.55, 0.70, 0.83, 0.59, 0.56
MutPred		0.24		Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);Loss of phosphorylation at S20 (P = 0.0047);
MVP		0.85
MPC		0.65
ClinPred		0.73	D
GERP RS		6.0
Varity_R		0.11
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057524801; hg19: chr15-93444526;