rs397515539

Positions:

• chr16-1459139-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001287.6(CLCN7):​c.643G>A​(p.Gly215Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLCN7 NM_001287.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.55

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 16-1459139-C-T is Pathogenic according to our data. Variant chr16-1459139-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 65635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1459139-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN7	NM_001287.6	c.643G>A	p.Gly215Arg	missense_variant	7/25	ENST00000382745.9	NP_001278.1
CLCN7	NM_001114331.3	c.571G>A	p.Gly191Arg	missense_variant	6/24		NP_001107803.1
CLCN7	XM_011522354.2	c.469G>A	p.Gly157Arg	missense_variant	7/25		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9	c.643G>A	p.Gly215Arg	missense_variant	7/25	1	NM_001287.6	ENSP00000372193	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460772 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 215 of the CLCN7 protein (p.Gly215Arg). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN7 function (PMID: 15111300). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLCN7 protein function. ClinVar contains an entry for this variant (Variation ID: 65635). This missense change has been observed in individuals with autosomal dominant osteopetrosis (PMID: 11741829). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2024	Published functional studies demonstrate reduced transport of chloride across the membrane suggesting a damaging effect on acidification during bone resorption (PMID: 19543743); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26325626, 14584882, 15111300, 19070589, 24336069, 20830208, 24185277, 31231577, 11741829, 27540713, 19953639, 23744590, 19288050, 26395888, 17164308, 36999084, 19543743) -

Autosomal dominant osteopetrosis 2 Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Lab, Department of Haematology, Christian Medical College	May 20, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

CLCN7-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2023

The CLCN7 c.643G>A variant is predicted to result in the amino acid substitution p.Gly215Arg. This variant has been reported in multiple individuals with autosomal dominant osteopetrosis and was reported to segregate with disease in at least one family (Table 1, Cleiren et al. 2001. PubMed ID: 11741829; Figure 1, Piret et al. 2016. PubMed ID: 27540713; Figure 3, Chen et al. 2023. PubMed ID: 36999084). In vitro experimental studies suggest this variant inhibits protein function and impacts the osteoclast acidification process (Figure 5, Henriksen et al. 2004. PubMed ID: 15111300; Figure 5, Kajiya et al. 2009. PubMed ID: 19543743). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.7	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.7	D;D;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.96
MutPred		0.97		Gain of MoRF binding (P = 0.0226);.;.;.;
MVP		0.95
MPC		1.7
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs397515539; hg19: chr16-1509140;