rs79302359

Positions:

• chr8-60795013-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017780.4(CHD7):​c.2124T>C​(p.Ser708=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0077 in 1,613,616 control chromosomes in the GnomAD database, including 307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (80 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (227 hom.)
• Consequence: CHD7 NM_017780.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.73

Genes affected

CHD7 (HGNC:20626): (chromodomain helicase DNA binding protein 7) This gene encodes a protein that contains several helicase family domains. Mutations in this gene have been found in some patients with the CHARGE syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 8-60795013-T-C is Benign according to our data. Variant chr8-60795013-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 95777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60795013-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.2124T>C	p.Ser708=	synonymous_variant	4/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.2124T>C	p.Ser708=	synonymous_variant	4/38	5	NM_017780.4	ENSP00000392028	P1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2885 AN: 152164 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0125 AC: 3107 AN: 248850 Hom.: 84 AF XY: 0.0139 AC XY: 1877 AN XY: 135028

Gnomad AFR exome AF: 0.0556

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.0492

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00652 AC: 9529 AN: 1461334 Hom.: 227 Cov.: 31 AF XY: 0.00785 AC XY: 5704 AN XY: 726920

Gnomad4 AFR exome AF: 0.0557

Gnomad4 AMR exome AF: 0.00468

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0498

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0190 AC: 2890 AN: 152282 Hom.: 80 Cov.: 32 AF XY: 0.0191 AC XY: 1425 AN XY: 74454

Gnomad4 AFR AF: 0.0552

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0429

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00262

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0100 Hom.: 18

Bravo AF: 0.0203

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 08, 2018	The p.Ser708Ser variant in CHD7 is classified as benign because it is present in 5.5% (1328/23984) of African chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2019	Variant summary: CHD7 c.2124T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 248850 control chromosomes in the gnomAD database, including 84 homozygotes. The observed variant frequency is approximately 9988.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHD7 causing Congenital Heart Disease phenotype (1.3e-06), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CHARGE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 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. -

CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	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: rs79302359; hg19: chr8-61707572;