rs117461525

chr16-1450500-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001287.6(CLCN7):c.1614G>A(p.Ala538=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.73

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]

ACMG classification

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/exons	MANE	UniProt
CLCN7	NM_001287.6	c.1614G>A	p.Ala538=	synonymous_variant	17/25	ENST00000382745.9
CLCN7	NM_001114331.3	c.1542G>A	p.Ala514=	synonymous_variant	16/24
CLCN7	XM_011522354.2	c.1440G>A	p.Ala480=	synonymous_variant	17/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN7	ENST00000382745.9	c.1614G>A	p.Ala538=	synonymous_variant	17/25	1	NM_001287.6	P1

Frequencies

GnomAD3 genomes AF: 0.0676 AC: 10291 AN: 152206 Hom.: 447 Cov.: 33

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

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.: 32 AF XY: 0.0912 AC XY: 65577 AN XY: 718746

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.: 33 AF XY: 0.0628 AC XY: 4681 AN XY: 74482

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: 47 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Osteopetrosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.59
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

Other links and lift over

dbSNP: rs117461525; hg19: chr16-1500501; COSMIC: COSV51970633; COSMIC: COSV51970633;