rs35280276

Positions:

• chr16-1460537-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001287.6(CLCN7):​c.485-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,601,914 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 0.13 (1472 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12795 hom.)
• Consequence: CLCN7 NM_001287.6 intron
• Scores: Splicing: ADA: 0.0003185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.167

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-1460537-A-G is Benign according to our data. Variant chr16-1460537-A-G is described in ClinVar as [Benign]. Clinvar id is 257956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1460537-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN7	NM_001287.6	c.485-10T>C		intron_variant		ENST00000382745.9	NP_001278.1
CLCN7	NM_001114331.3	c.413-10T>C		intron_variant			NP_001107803.1
CLCN7	XM_011522354.2	c.311-10T>C		intron_variant			XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9	c.485-10T>C		intron_variant		1	NM_001287.6	ENSP00000372193.4

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20268 AN: 152068 Hom.: 1470 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.00832

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0797

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.138

GnomAD3 exomes AF: 0.112 AC: 27998 AN: 249376 Hom.: 1768 AF XY: 0.114 AC XY: 15351 AN XY: 135018

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0815

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.00735

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.0849

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.129 AC: 186512 AN: 1449732 Hom.: 12795 Cov.: 28 AF XY: 0.128 AC XY: 92560 AN XY: 721864

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.0861

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.0172

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0902

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.133 AC: 20284 AN: 152182 Hom.: 1472 Cov.: 32 AF XY: 0.129 AC XY: 9570 AN XY: 74406

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.00835

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.0797

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.135

Alfa AF: 0.132 Hom.: 446

Bravo AF: 0.138

Asia WGS AF: 0.0550 AC: 190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

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	-0.89
CADD	Benign	8.4
DANN	Benign	0.55
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
SpliceAI score (max)		0.010		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: rs35280276; hg19: chr16-1510538;