rs12935737

Variant names:

• chr16-1454436-C-T
• rs12935737
• NM_001287.6:c.1128G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1454436-C-T
• chr16-1454436-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001287.6(CLCN7):​c.1128G>A​(p.Pro376Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,613,388 control chromosomes in the GnomAD database, including 7,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (446 hom., cov: 34)
  • Exomes 𝑓: 0.093 (7222 hom.)
• Consequence: CLCN7 NM_001287.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.360
• Publications: 11 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 16-1454436-C-T is Benign according to our data. Variant chr16-1454436-C-T is described in ClinVar as Benign. ClinVar VariationId is 257948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.36 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.1128G>A	p.Pro376Pro	synonymous	Exon 13 of 25	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.1056G>A	p.Pro352Pro	synonymous	Exon 12 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.1128G>A	p.Pro376Pro	synonymous	Exon 13 of 25	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.1056G>A	p.Pro352Pro	synonymous	Exon 12 of 24	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.1209G>A	p.Pro403Pro	synonymous	Exon 13 of 25	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.0677 AC: 10301 AN: 152180 Hom.: 446 Cov.: 34

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0743

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0996

Gnomad OTH AF: 0.0761

GnomAD2 exomes AF: 0.0663 AC: 16617 AN: 250802 AF XY: 0.0672

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.0469

Gnomad ASJ exome AF: 0.0842

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0982

Gnomad OTH exome AF: 0.0788

GnomAD4 exome AF: 0.0932 AC: 136117 AN: 1461090 Hom.: 7222 Cov.: 32 AF XY: 0.0913 AC XY: 66376 AN XY: 726836

African (AFR) AF: 0.0263 AC: 881 AN: 33474

American (AMR) AF: 0.0506 AC: 2263 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 2265 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39698

South Asian (SAS) AF: 0.0318 AC: 2746 AN: 86256

European-Finnish (FIN) AF: 0.0573 AC: 3035 AN: 52950

Middle Eastern (MID) AF: 0.0817 AC: 470 AN: 5754

European-Non Finnish (NFE) AF: 0.107 AC: 118983 AN: 1111724

Other (OTH) AF: 0.0905 AC: 5467 AN: 60378

GnomAD4 genome AF: 0.0676 AC: 10296 AN: 152298 Hom.: 446 Cov.: 34 AF XY: 0.0631 AC XY: 4695 AN XY: 74460

African (AFR) AF: 0.0282 AC: 1171 AN: 41578

American (AMR) AF: 0.0741 AC: 1134 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3470

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

South Asian (SAS) AF: 0.0339 AC: 164 AN: 4832

European-Finnish (FIN) AF: 0.0488 AC: 518 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0996 AC: 6773 AN: 68012

Other (OTH) AF: 0.0743 AC: 157 AN: 2112

Alfa AF: 0.0806 Hom.: 432

Bravo AF: 0.0698

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.104

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	-0.34
CADD	Benign	1.2
DANN	Benign	0.91
PhyloP100		-0.36
Mutation Taster		=97/3	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: rs12935737; hg19: chr16-1504437; COSMIC: COSV51970074; COSMIC: COSV51970074;