rs12926669

Positions:

• chr16-1452863-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001287.6(CLCN7):​c.1245T>C​(p.Ile415Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0963 in 1,578,122 control chromosomes in the GnomAD database, including 8,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (749 hom., cov: 33)
  • Exomes 𝑓: 0.097 (7419 hom.)
• Consequence: CLCN7 NM_001287.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.12

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-1452863-A-G is Benign according to our data. Variant chr16-1452863-A-G is described in ClinVar as [Benign]. Clinvar id is 257950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1452863-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN7	NM_001287.6	c.1245T>C	p.Ile415Ile	synonymous_variant	15/25	ENST00000382745.9	NP_001278.1
CLCN7	NM_001114331.3	c.1173T>C	p.Ile391Ile	synonymous_variant	14/24		NP_001107803.1
CLCN7	XM_011522354.2	c.1071T>C	p.Ile357Ile	synonymous_variant	15/25		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9	c.1245T>C	p.Ile415Ile	synonymous_variant	15/25	1	NM_001287.6	ENSP00000372193.4
CLCN7	ENST00000262318.12	c.1173T>C	p.Ile391Ile	synonymous_variant	14/24	5		ENSP00000262318.8
CLCN7	ENST00000699947.1	c.1245T>C	p.Ile415Ile	synonymous_variant	15/25			ENSP00000514703.1
CLCN7	ENST00000699948.1	n.1245T>C		non_coding_transcript_exon_variant	15/25			ENSP00000514704.1

Frequencies

GnomAD3 genomes AF: 0.0934 AC: 14208 AN: 152128 Hom.: 746 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0847

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0947

GnomAD3 exomes AF: 0.0707 AC: 13388 AN: 189294 Hom.: 568 AF XY: 0.0700 AC XY: 7185 AN XY: 102704

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0516

Gnomad ASJ exome AF: 0.0845

Gnomad EAS exome AF: 0.000215

Gnomad SAS exome AF: 0.0311

Gnomad FIN exome AF: 0.0520

Gnomad NFE exome AF: 0.0983

Gnomad OTH exome AF: 0.0852

GnomAD4 exome AF: 0.0966 AC: 137713 AN: 1425876 Hom.: 7419 Cov.: 32 AF XY: 0.0943 AC XY: 66605 AN XY: 706426

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.0568

Gnomad4 ASJ exome AF: 0.0870

Gnomad4 EAS exome AF: 0.000187

Gnomad4 SAS exome AF: 0.0322

Gnomad4 FIN exome AF: 0.0571

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.0963

GnomAD4 genome AF: 0.0934 AC: 14226 AN: 152246 Hom.: 749 Cov.: 33 AF XY: 0.0877 AC XY: 6527 AN XY: 74440

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0842

Gnomad4 ASJ AF: 0.0847

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0352

Gnomad4 FIN AF: 0.0489

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.0928

Alfa AF: 0.101 Hom.: 1060

Bravo AF: 0.0996

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2016	- -

Osteopetrosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.91
CADD	Benign	0.28
DANN	Benign	0.45
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

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: rs12926669; hg19: chr16-1502864; COSMIC: COSV51970429; COSMIC: COSV51970429;