rs201604061

chr14-21394474-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP6 BS1 BS2

The NM_001170629.2(CHD8):c.5402G>A(p.Arg1801His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000548 in 1,597,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: CHD8 NM_001170629.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHD8
• BP6: Variant 14-21394474-C-T is Benign according to our data. Variant chr14-21394474-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289377.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000368 (56/152240) while in subpopulation AMR AF= 0.000654 (10/15290). AF 95% confidence interval is 0.000431. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD8	NM_001170629.2	c.5402G>A	p.Arg1801His	missense_variant	31/38	ENST00000646647.2
CHD8	NM_020920.4	c.4565G>A	p.Arg1522His	missense_variant	31/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD8	ENST00000646647.2	c.5402G>A	p.Arg1801His	missense_variant	31/38		NM_001170629.2	P3

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000312 AC: 68 AN: 217978 Hom.: 0 AF XY: 0.000263 AC XY: 31 AN XY: 117724

Gnomad AFR exome AF: 0.0000755

Gnomad AMR exome AF: 0.000601

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: 0.000488

Gnomad OTH exome AF: 0.000360

GnomAD4 exome AF: 0.000567 AC: 820 AN: 1445122 Hom.: 0 Cov.: 34 AF XY: 0.000588 AC XY: 422 AN XY: 717528

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.000753

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000674

Gnomad4 OTH exome AF: 0.000668

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152240 Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27 AN XY: 74460

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000545 Hom.: 0

Bravo AF: 0.000423

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000216 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CHD8: PP2, PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2019	- -

Intellectual developmental disorder with autism and macrocephaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CHD8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D;D;.;.;D;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;D;.;.
Polyphen		1.0	D;.;.;D;.;.;.
Vest4		0.71
MVP		0.94
MPC		1.1
ClinPred		0.85	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.75

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

Other links and lift over

dbSNP: rs201604061; hg19: chr14-21862633;