rs6999971

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. P2045P) has been classified 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

Publications

6 publications found

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 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

CHD7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 158306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
CHD7	NM_017780.4 link	c.6135G>A	p.Pro2045Pro	synonymous_variant	Exon 31 of 38	ENST00000423902.7	NP_060250.2	Q9P2D1-1Q6ZWF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHD7	ENST00000423902.7 link	c.6135G>A	p.Pro2045Pro	synonymous_variant	Exon 31 of 38	5	NM_017780.4	ENSP00000392028.1	Q9P2D1-1
CHD7	ENST00000524602.5 link	c.1717-9369G>A		intron_variant	Intron 2 of 4	1		ENSP00000437061.1	Q9P2D1-4
CHD7	ENST00000695853.1 link	n.6135G>A		non_coding_transcript_exon_variant	Exon 31 of 37			ENSP00000512218.1	A0A8Q3WKT9
CHD7	ENST00000527921.1 link	n.*221G>A		downstream_gene_variant		4

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

GnomAD2 exomes

AF:

0.0310

AC:

7722

AN:

249082

AF XY:

0.0312

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 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

African (AFR)

AF:

0.00914

AC:

306

AN:

33468

American (AMR)

AF:

0.0248

AC:

1107

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0698

AC:

1824

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0105

AC:

905

AN:

86256

European-Finnish (FIN)

AF:

0.0413

AC:

2200

AN:

53276

Middle Eastern (MID)

AF:

0.0579

AC:

334

AN:

5768

European-Non Finnish (NFE)

AF:

0.0418

AC:

46516

AN:

1111586

Other (OTH)

AF:

0.0348

AC:

2102

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3344

6687

10031

13374

16718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1752

3504

5256

7008

8760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0301

AC:

4579

AN:

152180

Hom.:

103

Cov.:

AF XY:

0.0297

AC XY:

2206

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00942

AC:

391

AN:

41518

American (AMR)

AF:

0.0302

AC:

462

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0761

AC:

264

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00997

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0467

AC:

495

AN:

10592

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0400

AC:

2717

AN:

67998

Other (OTH)

AF:

0.0441

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

234

468

701

935

1169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0316

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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.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). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Jun 11, 2014

Eurofins Ntd Llc (ga)

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

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 02, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CHARGE syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 24, 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

-0.70

CADD

Benign

8.0

(source)

DANN

Benign

0.76

PhyloP100

-2.1

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over