rs11860968

Positions:

• chr16-1446612-T-C

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.*19A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,551,948 control chromosomes in the GnomAD database, including 8,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1233 hom., cov: 34)
  • Exomes 𝑓: 0.099 (7693 hom.)
• Consequence: CLCN7 NM_001287.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.496

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042717457).
• BP6: Variant 16-1446612-T-C is Benign according to our data. Variant chr16-1446612-T-C is described in ClinVar as [Benign]. Clinvar id is 257947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1446612-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN7	NM_001287.6	c.*19A>G		3_prime_UTR_variant	25/25	ENST00000382745.9
CLCN7	NM_001114331.3	c.*19A>G		3_prime_UTR_variant	24/24
CLCN7	XM_011522354.2	c.*19A>G		3_prime_UTR_variant	25/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN7	ENST00000382745.9	c.*19A>G		3_prime_UTR_variant	25/25	1	NM_001287.6	P1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17411 AN: 152064 Hom.: 1227 Cov.: 34

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0915

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0345

Gnomad FIN AF: 0.0486

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.0758 AC: 12296 AN: 162210 Hom.: 608 AF XY: 0.0734 AC XY: 6335 AN XY: 86322

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.0852

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.0328

Gnomad FIN exome AF: 0.0515

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0894

GnomAD4 exome AF: 0.0986 AC: 138032 AN: 1399766 Hom.: 7693 Cov.: 29 AF XY: 0.0961 AC XY: 66478 AN XY: 691400

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.0632

Gnomad4 ASJ exome AF: 0.0869

Gnomad4 EAS exome AF: 0.000167

Gnomad4 SAS exome AF: 0.0326

Gnomad4 FIN exome AF: 0.0571

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.115 AC: 17444 AN: 152182 Hom.: 1233 Cov.: 34 AF XY: 0.109 AC XY: 8088 AN XY: 74396

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.0913

Gnomad4 ASJ AF: 0.0850

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0354

Gnomad4 FIN AF: 0.0486

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.112

Alfa AF: 0.107 Hom.: 273

Bravo AF: 0.123

TwinsUK AF: 0.110 AC: 408

ALSPAC AF: 0.108 AC: 417

ESP6500AA AF: 0.184 AC: 794

ESP6500EA AF: 0.0990 AC: 844

ExAC AF: 0.0529 AC: 5990

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

- -

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_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.4
DANN	Benign	0.48
DEOGEN2	Benign	0.066	T
FATHMM_MKL	Benign	0.00028	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0043	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	-0.030	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.23	T
Vest4		0.012
GERP RS		1.5

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: rs11860968; hg19: chr16-1496613;