14-21385683-C-T

Position:

chr14-21385683-C-T

Variant summary

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

The NM_001170629.2(CHD8):c.7676G>A(p.Arg2559Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,551,844 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2559G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CHD8
NM_001170629.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.93

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:

LOC107984643 (HGNC:):

LOC107984643 links:

Genome browser will be placed here

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=0.19309512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CHD8	NM_001170629.2 linkuse as main transcript	c.7676G>A	p.Arg2559Lys	missense_variant	38/38	ENST00000646647.2
LOC107984643	XR_001750627.2 linkuse as main transcript	n.441+970C>T		intron_variant, non_coding_transcript_variant
CHD8	NM_020920.4 linkuse as main transcript	c.6839G>A	p.Arg2280Lys	missense_variant	38/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD8	ENST00000646647.2 linkuse as main transcript	c.7676G>A	p.Arg2559Lys	missense_variant	38/38		NM_001170629.2	P3	Q9HCK8-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690348

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:

9.27e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with CHD8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2559 of the CHD8 protein (p.Arg2559Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

.;T;T;.;T;T

Eigen

Benign

-0.032

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.83

.;T;.;T;.;.

M_CAP

Benign

0.055

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Uncertain

-0.065

MutationAssessor

Benign

0.0

.;N;N;.;N;N

MutationTaster

Benign

0.57

D;N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.48

N;N;.;.;N;.

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;D;.;.;D;.

Sift4G

Benign

0.99

T;T;.;.;T;.

Polyphen

0.24

B;.;.;B;.;.

Vest4

0.23

MutPred

0.18

.;Gain of ubiquitination at R2559 (P = 0.0054);Gain of ubiquitination at R2559 (P = 0.0054);.;Gain of ubiquitination at R2559 (P = 0.0054);Gain of ubiquitination at R2559 (P = 0.0054);

MVP

0.60

MPC

0.34

ClinPred

0.59

GERP RS

5.3

Varity_R

0.38

gMVP

0.23

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