16-1445133-G-GC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001287.6(CLCN7):c.*1497_*1498insG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 152,258 control chromosomes in the GnomAD database, including 83 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.029 (83 hom., cov: 32)
  • Exomes 𝑓: 0.063 (0 hom.)
• Consequence: CLCN7 NM_001287.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.12

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0287 (4372/152226) while in subpopulation NFE AF= 0.0419 (2849/67988). AF 95% confidence interval is 0.0406. There are 83 homozygotes in gnomad4. There are 2038 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 83 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN7	NM_001287.6	c.*1497_*1498insG		3_prime_UTR_variant	25/25	ENST00000382745.9
CLCN7	NM_001114331.3	c.*1497_*1498insG		3_prime_UTR_variant	24/24
CLCN7	XM_011522354.2	c.*1497_*1498insG		3_prime_UTR_variant	25/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN7	ENST00000382745.9	c.*1497_*1498insG		3_prime_UTR_variant	25/25	1	NM_001287.6	P1
CLCN7	ENST00000563642.6	n.3984_3985insG		non_coding_transcript_exon_variant	9/9	2

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4376 AN: 152110 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0292

GnomAD4 exome AF: 0.0625 AC: 2 AN: 32 Hom.: 0 Cov.: 0 AF XY: 0.0500 AC XY: 1 AN XY: 20

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0287 AC: 4372 AN: 152226 Hom.: 83 Cov.: 32 AF XY: 0.0274 AC XY: 2038 AN XY: 74424

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.0321

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.0419

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0321 Hom.: 10

Bravo AF: 0.0304

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteopetrosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs373942084; hg19: chr16-1495134;