8-60853001-G-A

Position:

• chr8-60853001-G-A

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.6276G>A​(p.Glu2092=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0534 in 1,613,912 control chromosomes in the GnomAD database, including 5,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2167 hom., cov: 32)
  • Exomes 𝑓: 0.047 (3034 hom.)
• Consequence: CHD7 NM_017780.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.44

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 8-60853001-G-A is Benign according to our data. Variant chr8-60853001-G-A is described in ClinVar as [Benign]. Clinvar id is 95802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60853001-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.6276G>A	p.Glu2092=	synonymous_variant	31/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.6276G>A	p.Glu2092=	synonymous_variant	31/38	5	NM_017780.4	P1
CHD7	ENST00000524602.5	c.1717-9228G>A		intron_variant		1
CHD7	ENST00000695853.1	c.6276G>A	p.Glu2092=	synonymous_variant, NMD_transcript_variant	31/37

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17995 AN: 152084 Hom.: 2170 Cov.: 32

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0637

Gnomad ASJ AF: 0.0688

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.0478

Gnomad FIN AF: 0.0756

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0406

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.0611 AC: 15230 AN: 249160 Hom.: 1081 AF XY: 0.0572 AC XY: 7733 AN XY: 135166

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.0359

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.0132

Gnomad SAS exome AF: 0.0464

Gnomad FIN exome AF: 0.0804

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0565

GnomAD4 exome AF: 0.0466 AC: 68184 AN: 1461710 Hom.: 3034 Cov.: 33 AF XY: 0.0458 AC XY: 33281 AN XY: 727138

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.0399

Gnomad4 ASJ exome AF: 0.0754

Gnomad4 EAS exome AF: 0.0165

Gnomad4 SAS exome AF: 0.0474

Gnomad4 FIN exome AF: 0.0784

Gnomad4 NFE exome AF: 0.0368

Gnomad4 OTH exome AF: 0.0592

GnomAD4 genome AF: 0.118 AC: 18002 AN: 152202 Hom.: 2167 Cov.: 32 AF XY: 0.117 AC XY: 8712 AN XY: 74412

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.0636

Gnomad4 ASJ AF: 0.0688

Gnomad4 EAS AF: 0.0159

Gnomad4 SAS AF: 0.0472

Gnomad4 FIN AF: 0.0756

Gnomad4 NFE AF: 0.0406

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0606 Hom.: 869

Bravo AF: 0.123

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.0376

EpiControl AF: 0.0381

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Glu2092Glu in exon 31 of CHD7: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 30.76% (3016/9804) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs2068096). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2018	- -

CHARGE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 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. -

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	2.1
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs2068096; hg19: chr8-61765560;