rs35939214

Positions:

• chr16-1448776-G-A
• chr16-1448776-G-C
• chr16-1448776-G-T

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.1798-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,609,856 control chromosomes in the GnomAD database, including 2,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (131 hom., cov: 33)
  • Exomes 𝑓: 0.047 (1917 hom.)
• Consequence: CLCN7 NM_001287.6 intron
• Scores: Splicing: ADA: 0.00002410
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.319

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=-0.82).
• BP6: Variant 16-1448776-G-A is Benign according to our data. Variant chr16-1448776-G-A is described in ClinVar as [Benign]. Clinvar id is 257953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1448776-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN7	NM_001287.6	c.1798-10C>T		intron_variant		ENST00000382745.9	NP_001278.1
CLCN7	NM_001114331.3	c.1726-10C>T		intron_variant			NP_001107803.1
CLCN7	XM_011522354.2	c.1624-10C>T		intron_variant			XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9	c.1798-10C>T		intron_variant		1	NM_001287.6	ENSP00000372193.4

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5313 AN: 152114 Hom.: 131 Cov.: 33

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0322 AC: 7954 AN: 247056 Hom.: 163 AF XY: 0.0320 AC XY: 4300 AN XY: 134362

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0385

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00722

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.0489

Gnomad OTH exome AF: 0.0352

GnomAD4 exome AF: 0.0467 AC: 68049 AN: 1457624 Hom.: 1917 Cov.: 35 AF XY: 0.0454 AC XY: 32950 AN XY: 725190

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.0230

Gnomad4 ASJ exome AF: 0.0404

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00731

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0543

Gnomad4 OTH exome AF: 0.0422

GnomAD4 genome AF: 0.0349 AC: 5311 AN: 152232 Hom.: 131 Cov.: 33 AF XY: 0.0331 AC XY: 2462 AN XY: 74440

Gnomad4 AFR AF: 0.0189

Gnomad4 AMR AF: 0.0387

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.0312

Gnomad4 NFE AF: 0.0498

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0302 Hom.: 32

Bravo AF: 0.0348

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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

-

- -

Increased bone mineral density Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 23, 2020

- -

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	-0.82
CADD	Benign	0.82
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
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: rs35939214; hg19: chr16-1498777;