rs12923538

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001287.6(CLCN7):c.660C>T(p.His220=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,611,256 control chromosomes in the GnomAD database, including 14,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1753 hom., cov: 34)

Exomes 𝑓: 0.13 ( 12514 hom. )

Consequence

CLCN7
NM_001287.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.80

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 16-1459122-G-A is Benign according to our data. Variant chr16-1459122-G-A is described in ClinVar as [Benign]. Clinvar id is 257957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1459122-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.8 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CLCN7	NM_001287.6 linkuse as main transcript	c.660C>T	p.His220=	synonymous_variant	7/25	ENST00000382745.9	NP_001278.1
CLCN7	NM_001114331.3 linkuse as main transcript	c.588C>T	p.His196=	synonymous_variant	6/24		NP_001107803.1
CLCN7	XM_011522354.2 linkuse as main transcript	c.486C>T	p.His162=	synonymous_variant	7/25		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9 linkuse as main transcript	c.660C>T	p.His220=	synonymous_variant	7/25	1	NM_001287.6	ENSP00000372193	P1	P51798-1

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21581

AN:

152160

Hom.:

1753

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.00867

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0799

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.144

GnomAD3 exomes

AF:

0.113

AC:

28041

AN:

248232

Hom.:

1818

AF XY:

0.114

AC XY:

15291

AN XY:

134692

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.0812

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.00736

Gnomad SAS exome

AF:

0.112

Gnomad FIN exome

AF:

0.0864

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.127

AC:

184761

AN:

1458978

Hom.:

12514

Cov.:

AF XY:

0.126

AC XY:

91439

AN XY:

725426

show subpopulations

Gnomad4 AFR exome

AF:

0.209

Gnomad4 AMR exome

AF:

0.0860

Gnomad4 ASJ exome

AF:

0.147

Gnomad4 EAS exome

AF:

0.0173

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.0914

Gnomad4 NFE exome

AF:

0.131

Gnomad4 OTH exome

AF:

0.135

GnomAD4 genome

AF:

0.142

AC:

21603

AN:

152278

Hom.:

1753

Cov.:

AF XY:

0.137

AC XY:

10232

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.205

Gnomad4 AMR

AF:

0.136

Gnomad4 ASJ

AF:

0.145

Gnomad4 EAS

AF:

0.00869

Gnomad4 SAS

AF:

0.109

Gnomad4 FIN

AF:

0.0799

Gnomad4 NFE

AF:

0.127

Gnomad4 OTH

AF:

0.141

Alfa

AF:

0.119

Hom.:

549

Bravo

AF:

0.148

Asia WGS

AF:

0.0540

AC:

189

AN:

3478

EpiCase

AF:

0.137

EpiControl

AF:

0.139

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 13, 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

2.0

DANN

Benign

0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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