rs2068096

Variant names:

• chr8-60853001-G-A
• rs2068096
• NM_017780.4:c.6276G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-60853001-G-A
• chr8-60853001-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017780.4(CHD7):​c.6276G>A​(p.Glu2092Glu) 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:14
• Conservation: PhyloP100: 1.44
• Publications: 9 publications found

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]

CHD7 Gene-Disease associations (from GenCC):

• CHARGE syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Broad Center for Mendelian Genomics, ClinGen, G2P
• hypogonadotropic hypogonadism 5 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 95802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.6276G>A	p.Glu2092Glu	synonymous_variant	Exon 31 of 38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.6276G>A	p.Glu2092Glu	synonymous_variant	Exon 31 of 38	5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1717-9228G>A		intron_variant	Intron 2 of 4	1		ENSP00000437061.1
CHD7	ENST00000695853.1	n.6276G>A		non_coding_transcript_exon_variant	Exon 31 of 37			ENSP00000512218.1

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

GnomAD2 exomes AF: 0.0611 AC: 15230 AN: 249160 AF XY: 0.0572

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 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

African (AFR) AF: 0.315 AC: 10553 AN: 33478

American (AMR) AF: 0.0399 AC: 1784 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0754 AC: 1971 AN: 26136

East Asian (EAS) AF: 0.0165 AC: 657 AN: 39700

South Asian (SAS) AF: 0.0474 AC: 4086 AN: 86258

European-Finnish (FIN) AF: 0.0784 AC: 4187 AN: 53402

Middle Eastern (MID) AF: 0.0706 AC: 407 AN: 5768

European-Non Finnish (NFE) AF: 0.0368 AC: 40965 AN: 1111870

Other (OTH) AF: 0.0592 AC: 3574 AN: 60374

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

African (AFR) AF: 0.305 AC: 12670 AN: 41500

American (AMR) AF: 0.0636 AC: 973 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0688 AC: 239 AN: 3472

East Asian (EAS) AF: 0.0159 AC: 82 AN: 5170

South Asian (SAS) AF: 0.0472 AC: 228 AN: 4826

European-Finnish (FIN) AF: 0.0756 AC: 802 AN: 10608

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0406 AC: 2760 AN: 68008

Other (OTH) AF: 0.102 AC: 216 AN: 2114

Alfa AF: 0.0671 Hom.: 1281

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Aug 03, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 24, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Jul 25, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CHARGE syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Mar 16, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs2068096; hg19: chr8-61765560;