14-21385470-ATTTTTT-ATTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001170629.2(CHD8):​c.*142delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 138,474 control chromosomes in the GnomAD database, including 417 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.047 (417 hom., cov: 31)
  • Exomes 𝑓: 0.28 (25 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHD8 NM_001170629.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 14-21385470-AT-A is Benign according to our data. Variant chr14-21385470-AT-A is described in ClinVar as Benign. ClinVar VariationId is 1183346.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

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.*142delA		3_prime_UTR	Exon 38 of 38	NP_001164100.1	Q9HCK8-1
	CHD8	NM_020920.4		c.*142delA		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.*142delA		3_prime_UTR	Exon 38 of 38	ENSP00000495240.1	Q9HCK8-1
	CHD8	ENST00000430710.8	TSL:1	c.*142delA		3_prime_UTR	Exon 38 of 38	ENSP00000406288.3	Q9HCK8-2
	CHD8	ENST00000864429.1		c.*142delA		3_prime_UTR	Exon 38 of 38	ENSP00000534488.1

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 6517 AN: 138444 Hom.: 415 Cov.: 31

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0128

Gnomad EAS AF: 0.00205

Gnomad SAS AF: 0.00137

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0135

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.0439

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.281 AC: 237779 AN: 845428 Hom.: 25 Cov.: 0 AF XY: 0.283 AC XY: 116926 AN XY: 412990

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

African (AFR) AF: 0.353 AC: 7127 AN: 20196

American (AMR) AF: 0.325 AC: 4668 AN: 14370

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 4232 AN: 13374

East Asian (EAS) AF: 0.325 AC: 8170 AN: 25116

South Asian (SAS) AF: 0.277 AC: 11697 AN: 42168

European-Finnish (FIN) AF: 0.319 AC: 7128 AN: 22330

Middle Eastern (MID) AF: 0.296 AC: 732 AN: 2472

European-Non Finnish (NFE) AF: 0.274 AC: 183366 AN: 669148

Other (OTH) AF: 0.294 AC: 10659 AN: 36254

⚠️ 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: 0.0472 AC: 6536 AN: 138474 Hom.: 417 Cov.: 31 AF XY: 0.0470 AC XY: 3148 AN XY: 66910

African (AFR) AF: 0.150 AC: 5720 AN: 38066

American (AMR) AF: 0.0219 AC: 304 AN: 13856

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 42 AN: 3270

East Asian (EAS) AF: 0.00205 AC: 10 AN: 4868

South Asian (SAS) AF: 0.00138 AC: 6 AN: 4358

European-Finnish (FIN) AF: 0.0115 AC: 91 AN: 7922

Middle Eastern (MID) AF: 0.0147 AC: 4 AN: 272

European-Non Finnish (NFE) AF: 0.00436 AC: 275 AN: 63090

Other (OTH) AF: 0.0442 AC: 84 AN: 1900

Alfa AF: 0.000130 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: COSV53522416; COSMIC: COSV53522416;