dbSNP rs778721199: CHD8:p.Asp3Asn (chr14-21431637-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001170629.2(CHD8):c.7G>A(p.Asp3Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000072 in 1,389,456 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: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CHD8
NM_001170629.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.74

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autism
Inheritance: AD Classification: STRONG Submitted by: G2P
intellectual developmental disorder with autism and macrocephaly
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
congenital myasthenic syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CHD8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.407808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD8	NM_001170629.2 link	c.7G>A	p.Asp3Asn	missense_variant	Exon 2 of 38	ENST00000646647.2	NP_001164100.1	Q9HCK8-1
CHD8	NM_020920.4 link	c.6+174G>A		intron_variant	Intron 2 of 37		NP_065971.2	Q9HCK8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD8	ENST00000646647.2 link	c.7G>A	p.Asp3Asn	missense_variant	Exon 2 of 38		NM_001170629.2	ENSP00000495240.1		Q9HCK8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000667

AC:

AN:

149872

AF XY:

0.0000125

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000160

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.20e-7

AC:

AN:

1389456

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

685974

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31744

American (AMR)

AF:

0.00

AC:

AN:

35750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25128

East Asian (EAS)

AF:

0.00

AC:

AN:

36010

South Asian (SAS)

AF:

0.00

AC:

AN:

79668

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1079282

Other (OTH)

AF:

0.00

AC:

AN:

58062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000902

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 02, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;T;T;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;.;.;.;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.41

T;T;T;T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.0

L;L;L;L;.;.

PhyloP100

6.7

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.2

N;.;N;.;.;.

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;.;D;.;.;.

Sift4G

Pathogenic

0.0

D;.;D;.;.;.

Vest4

0.38

MutPred

0.43

Loss of disorder (P = 0.1008);Loss of disorder (P = 0.1008);Loss of disorder (P = 0.1008);Loss of disorder (P = 0.1008);.;.;

MVP

0.60

MPC

1.0

ClinPred

0.79

GERP RS

4.6

PromoterAI

-0.093

Neutral

(source)

Varity_R

0.30

gMVP

0.72

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over