15-92901281-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001271.4(CHD2):​c.44T>C​(p.Leu15Pro) variant causes a missense change involving the alteration of a non-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

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.35
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 1 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=0.1506235).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHD2NM_001271.4 linkc.44T>C p.Leu15Pro missense_variant Exon 2 of 39 ENST00000394196.9 NP_001262.3 O14647-1
CHD2NM_001042572.3 linkc.44T>C p.Leu15Pro 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.44T>C p.Leu15Pro 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
Bravo
AF:
0.00000378

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
Sep 04, 2016
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CHD2-related disease. This sequence change replaces leucine with proline at codon 15 of the CHD2 protein (p.Leu15Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Uncertain
0.023
T
BayesDel_noAF
Benign
-0.21
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.058
.;.;T;.;.;T;.
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.087
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.79
T;T;T;T;T;T;T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.15
T;T;T;T;T;T;T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
0.34
.;N;N;.;.;.;N
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
0.050
.;.;N;.;.;.;N
REVEL
Benign
0.18
Sift
Uncertain
0.028
.;.;D;.;.;.;D
Sift4G
Benign
0.30
T;T;T;.;.;T;T
Polyphen
0.0
.;B;B;.;.;.;.
Vest4
0.16, 0.16, 0.12, 0.30, 0.22, 0.14
MutPred
0.21
Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);
MVP
0.74
MPC
0.77
ClinPred
0.33
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.15
gMVP
0.14

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1060503522; hg19: chr15-93444511; API