16-1445242-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001287.6(CLCN7):c.*1389A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.907 in 152,138 control chromosomes in the GnomAD database, including 62,626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.91 (62605 hom., cov: 31)
  • Exomes 𝑓: 0.92 (21 hom.)
• Consequence: CLCN7 NM_001287.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.67

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 16-1445242-T-G is Benign according to our data. Variant chr16-1445242-T-G is described in ClinVar as [Benign]. Clinvar id is 317912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN7	NM_001287.6	c.*1389A>C		3_prime_UTR_variant	25/25	ENST00000382745.9
CLCN7	NM_001114331.3	c.*1389A>C		3_prime_UTR_variant	24/24
CLCN7	XM_011522354.2	c.*1389A>C		3_prime_UTR_variant	25/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN7	ENST00000382745.9	c.*1389A>C		3_prime_UTR_variant	25/25	1	NM_001287.6	P1
CLCN7	ENST00000563642.6	n.3876A>C		non_coding_transcript_exon_variant	9/9	2

Frequencies

GnomAD3 genomes AF: 0.907 AC: 137858 AN: 151970 Hom.: 62554 Cov.: 31

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.974

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.944

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.902

Gnomad FIN AF: 0.904

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.891

Gnomad OTH AF: 0.909

GnomAD4 exome AF: 0.920 AC: 46 AN: 50 Hom.: 21 Cov.: 0 AF XY: 0.905 AC XY: 38 AN XY: 42

Gnomad4 AFR exome AF: 0.500

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.935

GnomAD4 genome AF: 0.907 AC: 137963 AN: 152088 Hom.: 62605 Cov.: 31 AF XY: 0.908 AC XY: 67488 AN XY: 74338

Gnomad4 AFR AF: 0.913

Gnomad4 AMR AF: 0.944

Gnomad4 ASJ AF: 0.944

Gnomad4 EAS AF: 0.947

Gnomad4 SAS AF: 0.903

Gnomad4 FIN AF: 0.904

Gnomad4 NFE AF: 0.890

Gnomad4 OTH AF: 0.903

Alfa AF: 0.900 Hom.: 10521

Bravo AF: 0.911

Asia WGS AF: 0.889 AC: 3091 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.98
Cadd	Benign	0.65
Dann	Benign	0.18

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: rs710900; hg19: chr16-1495243;