14-21385470-ATTTTTT-ATTTTTTT

Variant names:

• chr14-21385470-A-AT
• rs370612022
• NM_001170629.2:c.*142dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001170629.2(CHD8):​c.*142dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0808 in 1,043,612 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.093 (0 hom.)
• Consequence: CHD8 NM_001170629.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• Publications: 2 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

ENSG00000260830 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00231 (320/138724) while in subpopulation EAS AF = 0.00678 (33/4868). AF 95% confidence interval is 0.00496. There are 0 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 320 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.*142dupA		3_prime_UTR	Exon 38 of 38	NP_001164100.1	Q9HCK8-1
	CHD8	NM_020920.4		c.*142dupA		3_prime_UTR	Exon 38 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.*142dupA		3_prime_UTR	Exon 38 of 38	ENSP00000495240.1	Q9HCK8-1
	CHD8	ENST00000430710.8	TSL:1	c.*142dupA		3_prime_UTR	Exon 38 of 38	ENSP00000406288.3	Q9HCK8-2
	CHD8	ENST00000864429.1		c.*142dupA		3_prime_UTR	Exon 38 of 38	ENSP00000534488.1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 317 AN: 138696 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00676

Gnomad SAS AF: 0.00320

Gnomad FIN AF: 0.00476

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00582

GnomAD4 exome AF: 0.0929 AC: 84041 AN: 904888 Hom.: 0 Cov.: 0 AF XY: 0.0919 AC XY: 40711 AN XY: 443028

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0631 AC: 1360 AN: 21550

American (AMR) AF: 0.0773 AC: 1236 AN: 15994

Ashkenazi Jewish (ASJ) AF: 0.0750 AC: 1117 AN: 14894

East Asian (EAS) AF: 0.0768 AC: 2217 AN: 28856

South Asian (SAS) AF: 0.0924 AC: 4122 AN: 44594

European-Finnish (FIN) AF: 0.0703 AC: 1760 AN: 25036

Middle Eastern (MID) AF: 0.0856 AC: 229 AN: 2674

European-Non Finnish (NFE) AF: 0.0962 AC: 68533 AN: 712094

Other (OTH) AF: 0.0885 AC: 3467 AN: 39196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00231 AC: 320 AN: 138724 Hom.: 0 Cov.: 31 AF XY: 0.00239 AC XY: 160 AN XY: 67046

African (AFR) AF: 0.00168 AC: 64 AN: 38112

American (AMR) AF: 0.000793 AC: 11 AN: 13880

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 17 AN: 3274

East Asian (EAS) AF: 0.00678 AC: 33 AN: 4868

South Asian (SAS) AF: 0.00275 AC: 12 AN: 4358

European-Finnish (FIN) AF: 0.00476 AC: 38 AN: 7986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00212 AC: 134 AN: 63202

Other (OTH) AF: 0.00579 AC: 11 AN: 1900

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=99/1	polymorphism

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: rs370612022; hg19: chr14-21853629; COSMIC: COSV53523203;