rs12923538

Variant names:

• chr16-1459122-G-A
• rs12923538
• NM_001287.6:c.660C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-1459122-G-A
• chr16-1459122-G-C
• chr16-1459122-G-T

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.660C>T​(p.His220His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,611,256 control chromosomes in the GnomAD database, including 14,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1753 hom., cov: 34)
  • Exomes 𝑓: 0.13 (12514 hom.)
• Consequence: CLCN7 NM_001287.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.80
• Publications: 10 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 16-1459122-G-A is Benign according to our data. Variant chr16-1459122-G-A is described in ClinVar as Benign. ClinVar VariationId is 257957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 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.660C>T	p.His220His	synonymous	Exon 7 of 25	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.588C>T	p.His196His	synonymous	Exon 6 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.660C>T	p.His220His	synonymous	Exon 7 of 25	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.588C>T	p.His196His	synonymous	Exon 6 of 24	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.741C>T	p.His247His	synonymous	Exon 7 of 25	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21581 AN: 152160 Hom.: 1753 Cov.: 34

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0799

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.113 AC: 28041 AN: 248232 AF XY: 0.114

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.0812

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.00736

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.127 AC: 184761 AN: 1458978 Hom.: 12514 Cov.: 32 AF XY: 0.126 AC XY: 91439 AN XY: 725426

African (AFR) AF: 0.209 AC: 6985 AN: 33444

American (AMR) AF: 0.0860 AC: 3832 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3841 AN: 26124

East Asian (EAS) AF: 0.0173 AC: 686 AN: 39646

South Asian (SAS) AF: 0.112 AC: 9624 AN: 86118

European-Finnish (FIN) AF: 0.0914 AC: 4817 AN: 52724

Middle Eastern (MID) AF: 0.163 AC: 938 AN: 5760

European-Non Finnish (NFE) AF: 0.131 AC: 145876 AN: 1110326

Other (OTH) AF: 0.135 AC: 8162 AN: 60256

GnomAD4 genome AF: 0.142 AC: 21603 AN: 152278 Hom.: 1753 Cov.: 34 AF XY: 0.137 AC XY: 10232 AN XY: 74464

African (AFR) AF: 0.205 AC: 8512 AN: 41556

American (AMR) AF: 0.136 AC: 2085 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 502 AN: 3466

East Asian (EAS) AF: 0.00869 AC: 45 AN: 5178

South Asian (SAS) AF: 0.109 AC: 524 AN: 4828

European-Finnish (FIN) AF: 0.0799 AC: 848 AN: 10616

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8653 AN: 68016

Other (OTH) AF: 0.141 AC: 298 AN: 2116

Alfa AF: 0.119 Hom.: 549

Bravo AF: 0.148

Asia WGS AF: 0.0540 AC: 189 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.139

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	2.0
DANN	Benign	0.95
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	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: rs12923538; hg19: chr16-1509123; COSMIC: COSV51970655; COSMIC: COSV51970655;