15-92901277-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001271.4(CHD2):c.40T>G(p.Ser14Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S14S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.82

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CHD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.280779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD2	NM_001271.4	c.40T>G	p.Ser14Ala	missense_variant	2/39	ENST00000394196.9
CHD2	NM_001042572.3	c.40T>G	p.Ser14Ala	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD2	ENST00000394196.9	c.40T>G	p.Ser14Ala	missense_variant	2/39	5	NM_001271.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000189

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	Revvity Omics, Revvity	Oct 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 01, 2023	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 14 of the CHD2 protein (p.Ser14Ala). 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: 1017856). 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	Benign	0.078
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.51	T;T;T;T;T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
Sift4G	Benign	0.32	T;T;T;.;.;T;T
Polyphen		0.99, 0.98	.;D;D;.;.;.;.
Vest4		0.42, 0.39, 0.47, 0.62, 0.45, 0.40
MutPred		0.14		Loss of phosphorylation at S14 (P = 0.004);Loss of phosphorylation at S14 (P = 0.004);Loss of phosphorylation at S14 (P = 0.004);Loss of phosphorylation at S14 (P = 0.004);Loss of phosphorylation at S14 (P = 0.004);Loss of phosphorylation at S14 (P = 0.004);Loss of phosphorylation at S14 (P = 0.004);
MVP		0.79
MPC		0.39
ClinPred		0.59	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2052525047; hg19: chr15-93444507;