16-1450500-C-T

Variant names:

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.1614G>A(p.Ala538Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 1,599,812 control chromosomes in the GnomAD database, including 7,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 447 hom., cov: 33)

Exomes 𝑓: 0.093 ( 7098 hom. )

Consequence

CLCN7
NM_001287.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.73

Publications

6 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=-0.59).

BP6

Variant 16-1450500-C-T is Benign according to our data. Variant chr16-1450500-C-T is described in ClinVar as Benign. ClinVar VariationId is 257951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.73 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN7	NM_001287.6	MANE Select	c.1614G>A	p.Ala538Ala	synonymous	Exon 17 of 25	NP_001278.1
	CLCN7	NM_001114331.3		c.1542G>A	p.Ala514Ala	synonymous	Exon 16 of 24	NP_001107803.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCN7	ENST00000382745.9	TSL:1 MANE Select	c.1614G>A	p.Ala538Ala	synonymous	Exon 17 of 25	ENSP00000372193.4
CLCN7	ENST00000262318.12	TSL:5	c.1542G>A	p.Ala514Ala	synonymous	Exon 16 of 24	ENSP00000262318.8
CLCN7	ENST00000699947.1		c.1614G>A	p.Ala538Ala	synonymous	Exon 17 of 25	ENSP00000514703.1

Frequencies

GnomAD3 genomes

AF:

0.0676

AC:

10291

AN:

152206

Hom.:

447

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0280

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0762

Gnomad ASJ

AF:

0.0844

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0331

Gnomad FIN

AF:

0.0484

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0996

Gnomad OTH

AF:

0.0765

GnomAD2 exomes

AF:

0.0656

AC:

14737

AN:

224724

AF XY:

0.0669

show subpopulations

Gnomad AFR exome

AF:

0.0249

Gnomad AMR exome

AF:

0.0472

Gnomad ASJ exome

AF:

0.0833

Gnomad EAS exome

AF:

0.000176

Gnomad FIN exome

AF:

0.0528

Gnomad NFE exome

AF:

0.0981

Gnomad OTH exome

AF:

0.0800

GnomAD4 exome

AF:

0.0930

AC:

134644

AN:

1447488

Hom.:

7098

Cov.:

AF XY:

0.0912

AC XY:

65577

AN XY:

718746

show subpopulations

African (AFR)

AF:

0.0260

AC:

866

AN:

33324

American (AMR)

AF:

0.0516

AC:

2203

AN:

42696

Ashkenazi Jewish (ASJ)

AF:

0.0870

AC:

2243

AN:

25786

East Asian (EAS)

AF:

0.000204

AC:

AN:

39166

South Asian (SAS)

AF:

0.0314

AC:

2648

AN:

84326

European-Finnish (FIN)

AF:

0.0577

AC:

2931

AN:

50836

Middle Eastern (MID)

AF:

0.0802

AC:

441

AN:

5498

European-Non Finnish (NFE)

AF:

0.107

AC:

117885

AN:

1106000

Other (OTH)

AF:

0.0905

AC:

5419

AN:

59856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

6020

12040

18059

24079

30099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4278

8556

12834

17112

21390

<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:

0.0675

AC:

10286

AN:

152324

Hom.:

447

Cov.:

AF XY:

0.0628

AC XY:

4681

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0278

AC:

1158

AN:

41580

American (AMR)

AF:

0.0760

AC:

1163

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0844

AC:

293

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0342

AC:

165

AN:

4828

European-Finnish (FIN)

AF:

0.0484

AC:

514

AN:

10624

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0995

AC:

6771

AN:

68024

Other (OTH)

AF:

0.0747

AC:

158

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

516

1032

1549

2065

2581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0857

Hom.:

310

Bravo

AF:

0.0696

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Osteopetrosis

Benign:1

Jan 12, 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.17

(source)

DANN

Benign

0.92

PhyloP100

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over