15-92901269-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001271.4(CHD2):​c.32A>G​(p.Glu11Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

Frequency

Genomes: not found (cov: 31)

Consequence

CHD2
NM_001271.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.80
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the CHD2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 57 curated pathogenic missense variants (we use a threshold of 10). The gene has 104 curated benign missense variants. Gene score misZ: 5.2052 (above the threshold of 3.09). Trascript score misZ: 6.0204 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy 94, complex neurodevelopmental disorder, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHD2NM_001271.4 linkc.32A>G p.Glu11Gly missense_variant Exon 2 of 39 ENST00000394196.9 NP_001262.3 O14647-1
CHD2NM_001042572.3 linkc.32A>G p.Glu11Gly missense_variant Exon 2 of 13 NP_001036037.1 O14647-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHD2ENST00000394196.9 linkc.32A>G p.Glu11Gly missense_variant Exon 2 of 39 5 NM_001271.4 ENSP00000377747.4 O14647-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy 94 Uncertain:1
Jul 16, 2023
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 94 (MIM#615369). The mechanism of missense variants is unclear. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.10
.;.;T;.;.;T;.
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.81
T;T;T;T;T;T;T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.31
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.26
D
MutationAssessor
Benign
0.0
.;N;N;.;.;.;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.65
.;.;N;.;.;.;N
REVEL
Uncertain
0.35
Sift
Pathogenic
0.0
.;.;D;.;.;.;D
Sift4G
Benign
0.096
T;T;T;.;.;T;T
Polyphen
0.87, 0.80
.;P;P;.;.;.;.
Vest4
0.29, 0.27, 0.18, 0.31, 0.41, 0.31
MutPred
0.23
Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);
MVP
0.64
MPC
0.56
ClinPred
0.66
D
GERP RS
6.0
Varity_R
0.17
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.26
Position offset: 30

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-93444499; API