rs387907576

chr16-1461460-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001287.6(CLCN7):c.296A>G(p.Tyr99Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y99H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLCN7 NM_001287.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.87

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-1461461-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 452973.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 16-1461460-T-C is Pathogenic according to our data. Variant chr16-1461460-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN7	NM_001287.6	c.296A>G	p.Tyr99Cys	missense_variant	4/25	ENST00000382745.9
CLCN7	NM_001114331.3	c.224A>G	p.Tyr75Cys	missense_variant	3/24
CLCN7	XM_011522354.2	c.122A>G	p.Tyr41Cys	missense_variant	4/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN7	ENST00000382745.9	c.296A>G	p.Tyr99Cys	missense_variant	4/25	1	NM_001287.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2017	The Y99C variant in the CLCN7 gene has been reported previously in the heterozygous state in several unrelated individuals with osteopetrosis, including two families with segregation in multiple affected individuals (Del Fattore et al., 2006; Zheng et al., 2016; Sui et al., 2013). In addition, Y99C was reported in the homozygous state in a male child with infantile malignant osteopetrosis (Barvencik et al., 2014). The Y99C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y99C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The Y99C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 29, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 56890). This missense change has been observed in individuals with autosomal dominant osteopetrosis (PMID: 23296056, 26056022, 30229577). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 99 of the CLCN7 protein (p.Tyr99Cys). -

Autosomal dominant osteopetrosis 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Guangxi Key laboratory of Metabolic Diseases Research; Guilin 181st Hospital

-

- -

Autosomal recessive osteopetrosis 4 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;T;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D;D;D;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.88
MutPred		0.61		Loss of phosphorylation at Y99 (P = 0.0327);.;.;.;.;
MVP		0.97
MPC		1.7
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.89

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: rs387907576; hg19: chr16-1511461;