rs35939214

Variant names:

• chr16-1448776-G-A
• rs35939214
• NM_001287.6:c.1798-10C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1448776-G-A
• chr16-1448776-G-C
• chr16-1448776-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001287.6(CLCN7):​c.1798-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,609,856 control chromosomes in the GnomAD database, including 2,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (131 hom., cov: 33)
  • Exomes 𝑓: 0.047 (1917 hom.)
• Consequence: CLCN7 NM_001287.6 intron
• Scores: Splicing: ADA: 0.00002410
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.319
• Publications: 2 publications found

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]

CLCN7 Gene-Disease associations (from GenCC):

• autosomal dominant osteopetrosis 2

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• autosomal recessive osteopetrosis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp, Ambry Genetics
• hypopigmentation, organomegaly, and delayed myelination and development

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• autosomal recessive osteopetrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive osteopetrosis 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-1448776-G-A is Benign according to our data. Variant chr16-1448776-G-A is described in ClinVar as Benign. ClinVar VariationId is 257953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN7	NM_001287.6	c.1798-10C>T		intron_variant	Intron 19 of 24	ENST00000382745.9	NP_001278.1
CLCN7	NM_001114331.3	c.1726-10C>T		intron_variant	Intron 18 of 23		NP_001107803.1
CLCN7	XM_011522354.2	c.1624-10C>T		intron_variant	Intron 19 of 24		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9	c.1798-10C>T		intron_variant	Intron 19 of 24	1	NM_001287.6	ENSP00000372193.4

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5313 AN: 152114 Hom.: 131 Cov.: 33

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0498

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0322 AC: 7954 AN: 247056 AF XY: 0.0320

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0385

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.0489

Gnomad OTH exome AF: 0.0352

GnomAD4 exome AF: 0.0467 AC: 68049 AN: 1457624 Hom.: 1917 Cov.: 35 AF XY: 0.0454 AC XY: 32950 AN XY: 725190

African (AFR) AF: 0.0185 AC: 618 AN: 33468

American (AMR) AF: 0.0230 AC: 1029 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 1055 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.00731 AC: 630 AN: 86232

European-Finnish (FIN) AF: 0.0340 AC: 1707 AN: 50162

Middle Eastern (MID) AF: 0.0207 AC: 113 AN: 5472

European-Non Finnish (NFE) AF: 0.0543 AC: 60347 AN: 1111468

Other (OTH) AF: 0.0422 AC: 2546 AN: 60292

GnomAD4 genome AF: 0.0349 AC: 5311 AN: 152232 Hom.: 131 Cov.: 33 AF XY: 0.0331 AC XY: 2462 AN XY: 74440

African (AFR) AF: 0.0189 AC: 783 AN: 41532

American (AMR) AF: 0.0387 AC: 592 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4832

European-Finnish (FIN) AF: 0.0312 AC: 331 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0498 AC: 3384 AN: 67980

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0302 Hom.: 32

Bravo AF: 0.0348

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Increased bone mineral density Benign:1

Nov 23, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteopetrosis Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.82
CADD	Benign	0.82
DANN	Benign	0.79
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs35939214; hg19: chr16-1498777;