rs12923538

chr16-1459122-G-Achr16-1459122-G-T

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.660C>T(p.His220=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,611,256 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 0.14 (1753 hom., cov: 34)
  • Exomes 𝑓: 0.13 (12514 hom.)
• Consequence: CLCN7 NM_001287.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.80

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=-0.59).
• BP6: Variant 16-1459122-G-A is Benign according to our data. Variant chr16-1459122-G-A is described in ClinVar as [Benign]. Clinvar id is 257957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1459122-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN7	NM_001287.6	c.660C>T	p.His220=	synonymous_variant	7/25	ENST00000382745.9
CLCN7	NM_001114331.3	c.588C>T	p.His196=	synonymous_variant	6/24
CLCN7	XM_011522354.2	c.486C>T	p.His162=	synonymous_variant	7/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN7	ENST00000382745.9	c.660C>T	p.His220=	synonymous_variant	7/25	1	NM_001287.6	P1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21581 AN: 152160 Hom.: 1753 Cov.: 34

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0799

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.144

GnomAD3 exomes AF: 0.113 AC: 28041 AN: 248232 Hom.: 1818 AF XY: 0.114 AC XY: 15291 AN XY: 134692

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.0812

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.00736

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.127 AC: 184761 AN: 1458978 Hom.: 12514 Cov.: 32 AF XY: 0.126 AC XY: 91439 AN XY: 725426

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.0860

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.0173

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0914

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.142 AC: 21603 AN: 152278 Hom.: 1753 Cov.: 34 AF XY: 0.137 AC XY: 10232 AN XY: 74464

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.00869

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.0799

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.141

Alfa AF: 0.119 Hom.: 549

Bravo AF: 0.148

Asia WGS AF: 0.0540 AC: 189 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 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	-0.59
Cadd	Benign	2.0
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs12923538; hg19: chr16-1509123; COSMIC: COSV51970655; COSMIC: COSV51970655;