rs148706063

Positions:

• chr15-92943054-C-G
• chr15-92943054-C-T

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.1038C>G​(p.Asp346Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,576 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D346D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHD2 NM_001271.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.861

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=0.019313872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD2	NM_001271.4	c.1038C>G	p.Asp346Glu	missense_variant	9/39	ENST00000394196.9	NP_001262.3
CHD2	NM_001042572.3	c.1038C>G	p.Asp346Glu	missense_variant	9/13		NP_001036037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9	c.1038C>G	p.Asp346Glu	missense_variant	9/39	5	NM_001271.4	ENSP00000377747	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458576 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.6
DANN	Benign	0.85
DEOGEN2	Benign	0.051	.;T;T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.83	T;T;T;T;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.019	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.57	N;N;.;N;.;.
MutationTaster	Benign	0.59	D;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.42	.;N;.;N;.;.
REVEL	Benign	0.050
Sift	Benign	0.88	.;T;.;T;.;.
Sift4G	Benign	0.85	T;T;T;T;T;.
Polyphen		0.0010	B;B;.;.;B;.
Vest4		0.21
MutPred		0.31		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;Loss of helix (P = 0.0237);.;.;
MVP		0.27
MPC		0.45
ClinPred		0.057	T
GERP RS		0.33
Varity_R		0.014
gMVP		0.11

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs148706063; hg19: chr15-93486284;