chr14-21385752-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_001170629.2(CHD8):c.7607C>T(p.Pro2536Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CHD8
NM_001170629.2 missense
NM_001170629.2 missense
Scores
11
5
Clinical Significance
Conservation
PhyloP100: 3.00
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD8. . Trascript score misZ 7.0202 (greater than threshold 3.09). GenCC has associacion of gene with autism, intellectual disability, intellectual developmental disorder with autism and macrocephaly, congenital myasthenic syndrome, complex neurodevelopmental disorder.
BP4
Computational evidence support a benign effect (MetaRNN=0.23365933).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHD8 | NM_001170629.2 | c.7607C>T | p.Pro2536Leu | missense_variant | 38/38 | ENST00000646647.2 | |
LOC107984643 | XR_001750627.2 | n.441+1039G>A | intron_variant, non_coding_transcript_variant | ||||
CHD8 | NM_020920.4 | c.6770C>T | p.Pro2257Leu | missense_variant | 38/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHD8 | ENST00000646647.2 | c.7607C>T | p.Pro2536Leu | missense_variant | 38/38 | NM_001170629.2 | P3 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
GnomAD4 exome AF: 0.00000143 AC: 2AN: 1399530Hom.: 0 Cov.: 35 AF XY: 0.00000145 AC XY: 1AN XY: 690270
GnomAD4 exome
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2
AN:
1399530
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35
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AC XY:
1
AN XY:
690270
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GnomAD4 genome Cov.: 30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 12, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;.;N;.
REVEL
Uncertain
Sift
Uncertain
D;D;.;.;D;.
Sift4G
Uncertain
D;D;.;.;D;.
Polyphen
D;.;.;D;.;.
Vest4
MutPred
0.21
.;Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);.;Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);
MVP
MPC
0.31
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at