15-92901257-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001271.4(CHD2):​c.20A>G​(p.Lys7Arg) 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 (★).

Frequency

Genomes: not found (cov: 31)

Consequence

CHD2
NM_001271.4 missense

Scores

1
10
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.99
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 2 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.2652853).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHD2NM_001271.4 linkc.20A>G p.Lys7Arg missense_variant Exon 2 of 39 ENST00000394196.9 NP_001262.3 O14647-1
CHD2NM_001042572.3 linkc.20A>G p.Lys7Arg 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.20A>G p.Lys7Arg 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
Aug 08, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 7 of the CHD2 protein (p.Lys7Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant has not been reported in the literature in individuals with CHD2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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
0.083
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.066
.;.;T;.;.;T;.
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.86
D;D;D;T;T;D;D
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.27
T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Benign
0.69
.;N;N;.;.;.;N
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.49
.;.;N;.;.;.;N
REVEL
Uncertain
0.32
Sift
Pathogenic
0.0
.;.;D;.;.;.;D
Sift4G
Benign
0.40
T;T;T;.;.;T;T
Polyphen
0.72, 0.60
.;P;P;.;.;.;.
Vest4
0.43, 0.46, 0.33, 0.45, 0.45, 0.45
MutPred
0.26
Loss of ubiquitination at K7 (P = 0.0067);Loss of ubiquitination at K7 (P = 0.0067);Loss of ubiquitination at K7 (P = 0.0067);Loss of ubiquitination at K7 (P = 0.0067);Loss of ubiquitination at K7 (P = 0.0067);Loss of ubiquitination at K7 (P = 0.0067);Loss of ubiquitination at K7 (P = 0.0067);
MVP
0.59
MPC
0.39
ClinPred
0.61
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.22
gMVP
0.11

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2052524601; hg19: chr15-93444487; API