rs12926669

Variant names:

• chr16-1452863-A-G
• rs12926669
• NM_001287.6:c.1245T>C

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.1245T>C​(p.Ile415Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0963 in 1,578,122 control chromosomes in the GnomAD database, including 8,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (749 hom., cov: 33)
  • Exomes 𝑓: 0.097 (7419 hom.)
• Consequence: CLCN7 NM_001287.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.12
• Publications: 20 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

ENSG00000260051 (HGNC:58480):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-1452863-A-G is Benign according to our data. Variant chr16-1452863-A-G is described in ClinVar as Benign. ClinVar VariationId is 257950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 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.1245T>C	p.Ile415Ile	synonymous	Exon 15 of 25	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.1173T>C	p.Ile391Ile	synonymous	Exon 14 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.1245T>C	p.Ile415Ile	synonymous	Exon 15 of 25	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.1173T>C	p.Ile391Ile	synonymous	Exon 14 of 24	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.1326T>C	p.Ile442Ile	synonymous	Exon 15 of 25	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.0934 AC: 14208 AN: 152128 Hom.: 746 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0847

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0947

GnomAD2 exomes AF: 0.0707 AC: 13388 AN: 189294 AF XY: 0.0700

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0516

Gnomad ASJ exome AF: 0.0845

Gnomad EAS exome AF: 0.000215

Gnomad FIN exome AF: 0.0520

Gnomad NFE exome AF: 0.0983

Gnomad OTH exome AF: 0.0852

GnomAD4 exome AF: 0.0966 AC: 137713 AN: 1425876 Hom.: 7419 Cov.: 32 AF XY: 0.0943 AC XY: 66605 AN XY: 706426

African (AFR) AF: 0.119 AC: 3867 AN: 32436

American (AMR) AF: 0.0568 AC: 2290 AN: 40336

Ashkenazi Jewish (ASJ) AF: 0.0870 AC: 2223 AN: 25560

East Asian (EAS) AF: 0.000187 AC: 7 AN: 37404

South Asian (SAS) AF: 0.0322 AC: 2637 AN: 81998

European-Finnish (FIN) AF: 0.0571 AC: 2820 AN: 49360

Middle Eastern (MID) AF: 0.0888 AC: 509 AN: 5732

European-Non Finnish (NFE) AF: 0.108 AC: 117680 AN: 1094054

Other (OTH) AF: 0.0963 AC: 5680 AN: 58996

GnomAD4 genome AF: 0.0934 AC: 14226 AN: 152246 Hom.: 749 Cov.: 33 AF XY: 0.0877 AC XY: 6527 AN XY: 74440

African (AFR) AF: 0.116 AC: 4830 AN: 41536

American (AMR) AF: 0.0842 AC: 1288 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0847 AC: 294 AN: 3470

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

South Asian (SAS) AF: 0.0352 AC: 170 AN: 4824

European-Finnish (FIN) AF: 0.0489 AC: 519 AN: 10620

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6841 AN: 68004

Other (OTH) AF: 0.0928 AC: 196 AN: 2112

Alfa AF: 0.101 Hom.: 1312

Bravo AF: 0.0996

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.28
DANN	Benign	0.45
PhyloP100		-3.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs12926669; hg19: chr16-1502864; COSMIC: COSV51970429; COSMIC: COSV51970429;