Variant 14-21385626-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001170629.2(CHD8):c.7733A>G(p.Asp2578Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,399,104 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: 0.000011 ( 0 hom. )

Consequence

CHD8
NM_001170629.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.85

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]

CHD8 links:

CHD8 (HGNC:):

CHD8 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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=0.22652447).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD8	NM_001170629.2 linkuse as main transcript	c.7733A>G	p.Asp2578Gly	missense_variant	38/38	ENST00000646647.2	NP_001164100.1	Q9HCK8-1
CHD8	NM_020920.4 linkuse as main transcript	c.6896A>G	p.Asp2299Gly	missense_variant	38/38		NP_065971.2	Q9HCK8-2
LOC107984643	XR_001750627.2 linkuse as main transcript	n.441+913T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD8	ENST00000646647.2 linkuse as main transcript	c.7733A>G	p.Asp2578Gly	missense_variant	38/38		NM_001170629.2	ENSP00000495240.1		Q9HCK8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

157748

Hom.:

AF XY:

0.0000120

AC XY:

AN XY:

83180

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000325

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1399104

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

689966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000148

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.7733A>G (p.D2578G) alteration is located in exon 37 (coding exon 37) of the CHD8 gene. This alteration results from a A to G substitution at nucleotide position 7733, causing the aspartic acid (D) at amino acid position 2578 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;T;T;.;T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.82

.;T;.;T;.;.

M_CAP

Benign

0.065

MetaRNN

Benign

0.23

T;T;T;T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

0.0

.;N;N;.;N;N

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.25

N;N;.;.;N;.

REVEL

Uncertain

0.41

Sift

Uncertain

0.011

D;D;.;.;D;.

Sift4G

Benign

0.24

T;T;.;.;T;.

Polyphen

0.83

P;.;.;P;.;.

Vest4

0.20

MutPred

0.11

.;Loss of stability (P = 0.0494);Loss of stability (P = 0.0494);.;Loss of stability (P = 0.0494);Loss of stability (P = 0.0494);

MVP

0.80

MPC

0.77

ClinPred

0.54

GERP RS

5.3

Varity_R

0.21

gMVP

0.24

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over