rs201604061

Variant names:

• chr14-21394474-C-T
• rs201604061
• NM_001170629.2:c.5402G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. 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
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• 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 VariationId is 289377.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 56 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170629.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD8	NM_001170629.2	MANE Select	c.5402G>A	p.Arg1801His	missense	Exon 31 of 38	NP_001164100.1	Q9HCK8-1
	CHD8	NM_020920.4		c.4565G>A	p.Arg1522His	missense	Exon 31 of 38	NP_065971.2	Q9HCK8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD8	ENST00000646647.2	MANE Select	c.5402G>A	p.Arg1801His	missense	Exon 31 of 38	ENSP00000495240.1	Q9HCK8-1
	CHD8	ENST00000430710.8	TSL:1	c.4565G>A	p.Arg1522His	missense	Exon 31 of 38	ENSP00000406288.3	Q9HCK8-2
	CHD8	ENST00000557364.6	TSL:5	c.5402G>A	p.Arg1801His	missense	Exon 31 of 38	ENSP00000451601.1	Q9HCK8-1

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

GnomAD2 exomes AF: 0.000312 AC: 68 AN: 217978 AF XY: 0.000263

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 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

African (AFR) AF: 0.0000602 AC: 2 AN: 33218

American (AMR) AF: 0.000753 AC: 31 AN: 41166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 39136

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52590

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.000674 AC: 744 AN: 1103290

Other (OTH) AF: 0.000668 AC: 40 AN: 59918

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

African (AFR) AF: 0.000169 AC: 7 AN: 41524

American (AMR) AF: 0.000654 AC: 10 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000453 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	CHD8-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Intellectual developmental disorder with autism and macrocephaly (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	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
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs201604061; hg19: chr14-21862633;