Genetic Variant NM_001271.4:c.1038C>G (chr15-92943054-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D346G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CHD2
NM_001271.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.861

Publications

1 publications found

Variant links:

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]

CHD2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy 94
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
myoclonic-astatic epilepsy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

CHD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019313872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD2	NM_001271.4 link	c.1038C>G	p.Asp346Glu	missense_variant	Exon 9 of 39	ENST00000394196.9	NP_001262.3	O14647-1
CHD2	NM_001042572.3 link	c.1038C>G	p.Asp346Glu	missense_variant	Exon 9 of 13		NP_001036037.1	O14647-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD2	ENST00000394196.9 link	c.1038C>G	p.Asp346Glu	missense_variant	Exon 9 of 39	5	NM_001271.4	ENSP00000377747.4		O14647-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458576

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725788

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.0000224

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.00

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109294

Other (OTH)

AF:

0.00

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.6

(source)

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

LIST_S2

Benign

0.83

T;T;T;T;T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.019

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.57

N;N;.;N;.;.

PhyloP100

-0.86

PrimateAI

Benign

0.46

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

GERP RS

0.33

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.014

gMVP

0.11

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over