14-21402494-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001170629.2(CHD8):​c.3724C>T​(p.Arg1242Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

CHD8
NM_001170629.2 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.52
Variant links:
Genes affected
CHD8 (HGNC:20153): (chromodomain helicase DNA binding protein 8) This gene encodes a member of the chromodomain-helicase-DNA binding protein family, which is characterized by a SNF2-like domain and two chromatin organization modifier domains. The encoded protein also contains brahma and kismet domains, which are common to the subfamily of chromodomain-helicase-DNA binding proteins to which this protein belongs. This gene has been shown to function in several processes that include transcriptional regulation, epigenetic remodeling, promotion of cell proliferation, and regulation of RNA synthesis. Allelic variants of this gene are associated with autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2016]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-21402494-G-A is Pathogenic according to our data. Variant chr14-21402494-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 437423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHD8NM_001170629.2 linkuse as main transcriptc.3724C>T p.Arg1242Ter stop_gained 19/38 ENST00000646647.2
CHD8NM_020920.4 linkuse as main transcriptc.2887C>T p.Arg963Ter stop_gained 19/38

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHD8ENST00000646647.2 linkuse as main transcriptc.3724C>T p.Arg1242Ter stop_gained 19/38 NM_001170629.2 P3Q9HCK8-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de NantesMar 13, 2023- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJul 20, 2020For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg1242*) in the CHD8 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CHD8-related overgrowth syndrome (PMID: 31001818). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 437423). Loss-of-function variants in CHD8 are known to be pathogenic (PMID: 24998929, 26789910). -
Intellectual developmental disorder with autism and macrocephaly Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaSep 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
44
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.84
ClinPred
0.99
D
GERP RS
5.7

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: rs1555314788; hg19: chr14-21870653; API