rs6999971

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017780.4(CHD7):c.6135G>A(p.Pro2045Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,613,438 control chromosomes in the GnomAD database, including 1,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 103 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1215 hom. )

Consequence

CHD7
NM_017780.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -2.15

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 8-60852860-G-A is Benign according to our data. Variant chr8-60852860-G-A is described in ClinVar as [Benign]. Clinvar id is 158306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60852860-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.15 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4 linkuse as main transcript	c.6135G>A	p.Pro2045Pro	synonymous_variant	31/38	ENST00000423902.7	NP_060250.2	Q9P2D1-1Q6ZWF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CHD7	ENST00000423902.7 linkuse as main transcript	c.6135G>A	p.Pro2045Pro	synonymous_variant	31/38	5	NM_017780.4	ENSP00000392028.1	Q9P2D1-1
CHD7	ENST00000524602.5 linkuse as main transcript	c.1717-9369G>A		intron_variant		1		ENSP00000437061.1	Q9P2D1-4
CHD7	ENST00000695853.1 linkuse as main transcript	n.6135G>A		non_coding_transcript_exon_variant	31/37			ENSP00000512218.1	A0A8Q3WKT9

Frequencies

GnomAD3 genomes

AF:

0.0301

AC:

4581

AN:

152062

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00945

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.0303

Gnomad ASJ

AF:

0.0761

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00975

Gnomad FIN

AF:

0.0467

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0400

Gnomad OTH

AF:

0.0445

GnomAD3 exomes

AF:

0.0310

AC:

7722

AN:

249082

Hom.:

169

AF XY:

0.0312

AC XY:

4217

AN XY:

135140

show subpopulations

Gnomad AFR exome

AF:

0.00846

Gnomad AMR exome

AF:

0.0240

Gnomad ASJ exome

AF:

0.0726

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0101

Gnomad FIN exome

AF:

0.0441

Gnomad NFE exome

AF:

0.0400

Gnomad OTH exome

AF:

0.0418

GnomAD4 exome

AF:

0.0378

AC:

55294

AN:

1461258

Hom.:

1215

Cov.:

AF XY:

0.0372

AC XY:

27054

AN XY:

726810

show subpopulations

Gnomad4 AFR exome

AF:

0.00914

Gnomad4 AMR exome

AF:

0.0248

Gnomad4 ASJ exome

AF:

0.0698

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0105

Gnomad4 FIN exome

AF:

0.0413

Gnomad4 NFE exome

AF:

0.0418

Gnomad4 OTH exome

AF:

0.0348

GnomAD4 genome

AF:

0.0301

AC:

4579

AN:

152180

Hom.:

103

Cov.:

AF XY:

0.0297

AC XY:

2206

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00942

Gnomad4 AMR

AF:

0.0302

Gnomad4 ASJ

AF:

0.0761

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00997

Gnomad4 FIN

AF:

0.0467

Gnomad4 NFE

AF:

0.0400

Gnomad4 OTH

AF:

0.0441

Alfa

AF:

0.0335

Hom.:

Bravo

AF:

0.0283

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0451

EpiControl

AF:

0.0443

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Eurofins Ntd Llc (ga)	Jun 11, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Pro2045Pro 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 4.35% (288/6614) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs6999971). -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 02, 2018	- -

CHARGE syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 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

-0.70

CADD

Benign

8.0

DANN

Benign

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over