rs117461525

Variant names:

• chr16-1450500-C-T
• rs117461525
• NM_001287.6:c.1614G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1450500-C-T
• chr16-1450500-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001287.6(CLCN7):​c.1614G>A​(p.Ala538Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 1,599,812 control chromosomes in the GnomAD database, including 7,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (447 hom., cov: 33)
  • Exomes 𝑓: 0.093 (7098 hom.)
• Consequence: CLCN7 NM_001287.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.73
• Publications: 6 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: Ambry Genetics, ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive osteopetrosis 4

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

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-1450500-C-T is Benign according to our data. Variant chr16-1450500-C-T is described in ClinVar as Benign. ClinVar VariationId is 257951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN7	NM_001287.6	MANE Select	c.1614G>A	p.Ala538Ala	synonymous	Exon 17 of 25	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.1542G>A	p.Ala514Ala	synonymous	Exon 16 of 24	NP_001107803.1	P51798-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN7	ENST00000382745.9	TSL:1 MANE Select	c.1614G>A	p.Ala538Ala	synonymous	Exon 17 of 25	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.1542G>A	p.Ala514Ala	synonymous	Exon 16 of 24	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.1695G>A	p.Ala565Ala	synonymous	Exon 17 of 25	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.0676 AC: 10291 AN: 152206 Hom.: 447 Cov.: 33

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0762

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.0484

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0996

Gnomad OTH AF: 0.0765

GnomAD2 exomes AF: 0.0656 AC: 14737 AN: 224724 AF XY: 0.0669

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.0472

Gnomad ASJ exome AF: 0.0833

Gnomad EAS exome AF: 0.000176

Gnomad FIN exome AF: 0.0528

Gnomad NFE exome AF: 0.0981

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.0930 AC: 134644 AN: 1447488 Hom.: 7098 Cov.: 32 AF XY: 0.0912 AC XY: 65577 AN XY: 718746

African (AFR) AF: 0.0260 AC: 866 AN: 33324

American (AMR) AF: 0.0516 AC: 2203 AN: 42696

Ashkenazi Jewish (ASJ) AF: 0.0870 AC: 2243 AN: 25786

East Asian (EAS) AF: 0.000204 AC: 8 AN: 39166

South Asian (SAS) AF: 0.0314 AC: 2648 AN: 84326

European-Finnish (FIN) AF: 0.0577 AC: 2931 AN: 50836

Middle Eastern (MID) AF: 0.0802 AC: 441 AN: 5498

European-Non Finnish (NFE) AF: 0.107 AC: 117885 AN: 1106000

Other (OTH) AF: 0.0905 AC: 5419 AN: 59856

GnomAD4 genome AF: 0.0675 AC: 10286 AN: 152324 Hom.: 447 Cov.: 33 AF XY: 0.0628 AC XY: 4681 AN XY: 74482

African (AFR) AF: 0.0278 AC: 1158 AN: 41580

American (AMR) AF: 0.0760 AC: 1163 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0844 AC: 293 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0342 AC: 165 AN: 4828

European-Finnish (FIN) AF: 0.0484 AC: 514 AN: 10624

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0995 AC: 6771 AN: 68024

Other (OTH) AF: 0.0747 AC: 158 AN: 2114

Alfa AF: 0.0857 Hom.: 310

Bravo AF: 0.0696

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.17
DANN	Benign	0.92
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117461525; hg19: chr16-1500501; COSMIC: COSV51970633; COSMIC: COSV51970633;