16-1450500-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 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=-0.59).

BP6

Variant 16-1450500-C-T is Benign according to our data. Variant chr16-1450500-C-T is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN7	NM_001287.6 link	c.1614G>A	p.Ala538Ala	synonymous_variant	Exon 17 of 25	ENST00000382745.9	NP_001278.1	P51798-1
CLCN7	NM_001114331.3 link	c.1542G>A	p.Ala514Ala	synonymous_variant	Exon 16 of 24		NP_001107803.1	P51798-2
CLCN7	XM_011522354.2 link	c.1440G>A	p.Ala480Ala	synonymous_variant	Exon 17 of 25		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9 link	c.1614G>A	p.Ala538Ala	synonymous_variant	Exon 17 of 25	1	NM_001287.6	ENSP00000372193.4		P51798-1

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

GnomAD3 exomes

AF:

0.0656

AC:

14737

AN:

224724

Hom.:

593

AF XY:

0.0669

AC XY:

8154

AN XY:

121960

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 SAS exome

AF:

0.0304

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

Gnomad4 AFR exome

AF:

0.0260

Gnomad4 AMR exome

AF:

0.0516

Gnomad4 ASJ exome

AF:

0.0870

Gnomad4 EAS exome

AF:

0.000204

Gnomad4 SAS exome

AF:

0.0314

Gnomad4 FIN exome

AF:

0.0577

Gnomad4 NFE exome

AF:

0.107

Gnomad4 OTH exome

AF:

0.0905

GnomAD4 genome

AF:

0.0675

AC:

10286

AN:

152324

Hom.:

447

Cov.:

AF XY:

0.0628

AC XY:

4681

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0278

Gnomad4 AMR

AF:

0.0760

Gnomad4 ASJ

AF:

0.0844

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0342

Gnomad4 FIN

AF:

0.0484

Gnomad4 NFE

AF:

0.0995

Gnomad4 OTH

AF:

0.0747

Alfa

AF:

0.0860

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.17

DANN

Benign

0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

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