14-21385694-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001170629.2(CHD8):c.7665T>C(p.Asp2555=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,551,912 control chromosomes in the GnomAD database, including 423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 31)
  • Exomes 𝑓: 0.023 (399 hom.)
• Consequence: CHD8 NM_001170629.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.22

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]

LOC107984643 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 14-21385694-A-G is Benign according to our data. Variant chr14-21385694-A-G is described in ClinVar as [Benign]. Clinvar id is 587884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21385694-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0158 (2412/152210) while in subpopulation NFE AF= 0.0256 (1744/67996). AF 95% confidence interval is 0.0246. There are 24 homozygotes in gnomad4. There are 1130 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 2412 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD8	NM_001170629.2	c.7665T>C	p.Asp2555=	synonymous_variant	38/38	ENST00000646647.2
LOC107984643	XR_001750627.2	n.441+981A>G		intron_variant, non_coding_transcript_variant
CHD8	NM_020920.4	c.6828T>C	p.Asp2276=	synonymous_variant	38/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD8	ENST00000646647.2	c.7665T>C	p.Asp2555=	synonymous_variant	38/38		NM_001170629.2	P3

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2412 AN: 152092 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.00377

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0163 AC: 2577 AN: 158224 Hom.: 31 AF XY: 0.0156 AC XY: 1302 AN XY: 83362

Gnomad AFR exome AF: 0.00293

Gnomad AMR exome AF: 0.00741

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.0259

Gnomad NFE exome AF: 0.0275

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0231 AC: 32283 AN: 1399702 Hom.: 399 Cov.: 35 AF XY: 0.0227 AC XY: 15639 AN XY: 690332

Gnomad4 AFR exome AF: 0.00383

Gnomad4 AMR exome AF: 0.00697

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00312

Gnomad4 FIN exome AF: 0.0266

Gnomad4 NFE exome AF: 0.0269

Gnomad4 OTH exome AF: 0.0174

GnomAD4 genome AF: 0.0158 AC: 2412 AN: 152210 Hom.: 24 Cov.: 31 AF XY: 0.0152 AC XY: 1130 AN XY: 74444

Gnomad4 AFR AF: 0.00375

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0241

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0223 Hom.: 15

Bravo AF: 0.0145

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2016

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	6.1
Dann	Benign	0.81

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: rs61748933; hg19: chr14-21853853;