rs2235579

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_001287.6(CLCN7):c.1170A>T(p.Ala390Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,612,790 control chromosomes in the GnomAD database, including 214,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 20872 hom., cov: 35)

Exomes 𝑓: 0.51 ( 193255 hom. )

Consequence

CLCN7
NM_001287.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.59

Publications

31 publications found

Variant links:

Genes affected

CLCN7 (HGNC:2025): (chloride voltage-gated channel 7) The product of this gene belongs to the CLC chloride channel family of proteins. Chloride channels play important roles in the plasma membrane and in intracellular organelles. This gene encodes chloride channel 7. Defects in this gene are the cause of osteopetrosis autosomal recessive type 4 (OPTB4), also called infantile malignant osteopetrosis type 2 as well as the cause of autosomal dominant osteopetrosis type 2 (OPTA2), also called autosomal dominant Albers-Schonberg disease or marble disease autosoml dominant. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. OPTA2 is the most common form of osteopetrosis, occurring in adolescence or adulthood. [provided by RefSeq, Jul 2008]

CLCN7 Gene-Disease associations (from GenCC):

autosomal dominant osteopetrosis 2
Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
autosomal recessive osteopetrosis 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp, Ambry Genetics
hypopigmentation, organomegaly, and delayed myelination and development
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
autosomal recessive osteopetrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive osteopetrosis 6
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLCN7 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=-0.82).

BP6

Variant 16-1453878-T-A is Benign according to our data. Variant chr16-1453878-T-A is described in ClinVar as Benign. ClinVar VariationId is 257949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.59 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN7	NM_001287.6 link	c.1170A>T	p.Ala390Ala	synonymous_variant	Exon 14 of 25	ENST00000382745.9	NP_001278.1	P51798-1
CLCN7	NM_001114331.3 link	c.1098A>T	p.Ala366Ala	synonymous_variant	Exon 13 of 24		NP_001107803.1	P51798-2
CLCN7	XM_011522354.2 link	c.996A>T	p.Ala332Ala	synonymous_variant	Exon 14 of 25		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9 link	c.1170A>T	p.Ala390Ala	synonymous_variant	Exon 14 of 25	1	NM_001287.6	ENSP00000372193.4		P51798-1

Frequencies

GnomAD3 genomes

AF:

0.520

AC:

79105

AN:

152094

Hom.:

20843

Cov.:

show subpopulations

Gnomad AFR

AF:

0.518

Gnomad AMI

AF:

0.700

Gnomad AMR

AF:

0.534

Gnomad ASJ

AF:

0.520

Gnomad EAS

AF:

0.689

Gnomad SAS

AF:

0.560

Gnomad FIN

AF:

0.548

Gnomad MID

AF:

0.541

Gnomad NFE

AF:

0.495

Gnomad OTH

AF:

0.519

GnomAD2 exomes

AF:

0.534

AC:

133950

AN:

250664

AF XY:

0.531

show subpopulations

Gnomad AFR exome

AF:

0.522

Gnomad AMR exome

AF:

0.572

Gnomad ASJ exome

AF:

0.498

Gnomad EAS exome

AF:

0.665

Gnomad FIN exome

AF:

0.547

Gnomad NFE exome

AF:

0.502

Gnomad OTH exome

AF:

0.530

GnomAD4 exome

AF:

0.512

AC:

748269

AN:

1460578

Hom.:

193255

Cov.:

AF XY:

0.513

AC XY:

372661

AN XY:

726598

show subpopulations

African (AFR)

AF:

0.520

AC:

17420

AN:

33474

American (AMR)

AF:

0.563

AC:

25163

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.502

AC:

13112

AN:

26132

East Asian (EAS)

AF:

0.702

AC:

27869

AN:

39698

South Asian (SAS)

AF:

0.541

AC:

46665

AN:

86256

European-Finnish (FIN)

AF:

0.551

AC:

28916

AN:

52472

Middle Eastern (MID)

AF:

0.563

AC:

3247

AN:

5768

European-Non Finnish (NFE)

AF:

0.498

AC:

554082

AN:

1111698

Other (OTH)

AF:

0.527

AC:

31795

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

20527

41053

61580

82106

102633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16302

32604

48906

65208

81510

<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:

0.520

AC:

79180

AN:

152212

Hom.:

20872

Cov.:

AF XY:

0.523

AC XY:

38930

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.519

AC:

21535

AN:

41526

American (AMR)

AF:

0.535

AC:

8181

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.520

AC:

1805

AN:

3470

East Asian (EAS)

AF:

0.689

AC:

3561

AN:

5168

South Asian (SAS)

AF:

0.562

AC:

2714

AN:

4832

European-Finnish (FIN)

AF:

0.548

AC:

5813

AN:

10614

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.495

AC:

33677

AN:

67980

Other (OTH)

AF:

0.517

AC:

1092

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

2070

4140

6210

8280

10350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.467

Hom.:

4978

Bravo

AF:

0.524

Asia WGS

AF:

0.621

AC:

2155

AN:

3478

EpiCase

AF:

0.507

EpiControl

AF:

0.506

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

not provided

Benign:3

Nov 10, 2018

GeneDx

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypopigmentation, organomegaly, and delayed myelination and development

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive osteopetrosis 4

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant osteopetrosis 2

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteopetrosis

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

-0.82

CADD

Benign

0.36

(source)

DANN

Benign

0.82

PhyloP100

-2.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Mutation Taster

=99/1

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