rs35021217

chr16-1447639-G-A

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.2073+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,553,366 control chromosomes in the GnomAD database, including 7,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (453 hom., cov: 33)
  • Exomes 𝑓: 0.094 (7016 hom.)
• Consequence: CLCN7 NM_001287.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.60

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 (BayesDel_noAF=-0.91).
• BP6: Variant 16-1447639-G-A is Benign according to our data. Variant chr16-1447639-G-A is described in ClinVar as [Benign]. Clinvar id is 257955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1447639-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN7	NM_001287.6	c.2073+16C>T		intron_variant		ENST00000382745.9
CLCN7	NM_001114331.3	c.2001+16C>T		intron_variant
CLCN7	XM_011522354.2	c.1899+16C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN7	ENST00000382745.9	c.2073+16C>T		intron_variant		1	NM_001287.6	P1

Frequencies

GnomAD3 genomes AF: 0.0685 AC: 10424 AN: 152154 Hom.: 453 Cov.: 33

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0775

Gnomad ASJ AF: 0.0847

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0783

GnomAD3 exomes AF: 0.0647 AC: 10028 AN: 154990 Hom.: 399 AF XY: 0.0646 AC XY: 5372 AN XY: 83180

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.0508

Gnomad ASJ exome AF: 0.0846

Gnomad EAS exome AF: 0.000174

Gnomad SAS exome AF: 0.0317

Gnomad FIN exome AF: 0.0511

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.0835

GnomAD4 exome AF: 0.0943 AC: 132104 AN: 1401094 Hom.: 7016 Cov.: 35 AF XY: 0.0924 AC XY: 63870 AN XY: 691446

Gnomad4 AFR exome AF: 0.0266

Gnomad4 AMR exome AF: 0.0557

Gnomad4 ASJ exome AF: 0.0874

Gnomad4 EAS exome AF: 0.000195

Gnomad4 SAS exome AF: 0.0323

Gnomad4 FIN exome AF: 0.0567

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.0915

GnomAD4 genome AF: 0.0684 AC: 10419 AN: 152272 Hom.: 453 Cov.: 33 AF XY: 0.0638 AC XY: 4752 AN XY: 74466

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.0773

Gnomad4 ASJ AF: 0.0847

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0353

Gnomad4 FIN AF: 0.0483

Gnomad4 NFE AF: 0.100

Gnomad4 OTH AF: 0.0766

Alfa AF: 0.0876 Hom.: 145

Bravo AF: 0.0707

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	Jun 18, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.019
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs35021217; hg19: chr16-1497640;