rs1555439526

Positions:

• chr15-92942894-G-A
• chr15-92942894-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001271.4(CHD2):​c.878G>A​(p.Ser293Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.66

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD2. . Gene score misZ 5.2052 (greater than the threshold 3.09). Trascript score misZ 6.0204 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy 94, complex neurodevelopmental disorder, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03181395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4	c.878G>A	p.Ser293Asn	missense_variant	9/39	ENST00000394196.9	NP_001262.3
CHD2	NM_001042572.3	c.878G>A	p.Ser293Asn	missense_variant	9/13		NP_001036037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.878G>A	p.Ser293Asn	missense_variant	9/39	5	NM_001271.4	ENSP00000377747	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727170

Gnomad4 AFR exome AF: 0.0000299

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 Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 29, 2023	This variant has not been reported in the literature in individuals affected with CHD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 293 of the CHD2 protein (p.Ser293Asn). ClinVar contains an entry for this variant (Variation ID: 474399). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 23, 2020	The c.878G>A (p.Ser293Asn) variant substitutes a highly conserved Serine for Asparagine at amino acid 293/1829 (coding exon 9/39).This variant is absent from gnomAD suggesting it is not a common benign variant in the populations represented in this database. In silicoalgorithms predict this variant to be Neutral (Provean; score: 2.83) and Tolerated (SIFT; score: 1.000) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID: 474399), and to our current knowledge has not been reported in affected individuals in the literature. The p.Ser293 residue is within the first Chromodomainof CHD2 which is thought to be involved in chromatin remodeling activity [PMID: 25384982]. Given the lack of compelling evidence for its pathogenicity, the c.878G>A (p.Ser293Asn) variant is reported here as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	21
DANN	Benign	0.23
DEOGEN2	Benign	0.15	.;T;T;.;T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.76	T;T;D;T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.032	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.5	N;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	2.8	.;N;.;N;.;.
REVEL	Benign	0.14
Sift	Benign	1.0	.;T;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;.
Polyphen		0.0010	B;B;.;.;B;.
Vest4		0.14
MutPred		0.32		Loss of glycosylation at S293 (P = 0.0027);Loss of glycosylation at S293 (P = 0.0027);.;Loss of glycosylation at S293 (P = 0.0027);.;.;
MVP		0.30
MPC		0.45
ClinPred		0.081	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.12

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555439526; hg19: chr15-93486124;