rs12926089

Variant names:

• chr16-1452856-C-T
• rs12926089
• NM_001287.6:c.1252G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1452856-C-T
• chr16-1452856-C-A

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.1252G>A​(p.Val418Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,579,520 control chromosomes in the GnomAD database, including 9,189 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V418T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1094 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8095 hom.)
• Consequence: CLCN7 NM_001287.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.787
• Publications: 46 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019082427).
• BP6: Variant 16-1452856-C-T is Benign according to our data. Variant chr16-1452856-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 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.1252G>A	p.Val418Met	missense	Exon 15 of 25	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.1180G>A	p.Val394Met	missense	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.1252G>A	p.Val418Met	missense	Exon 15 of 25	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.1180G>A	p.Val394Met	missense	Exon 14 of 24	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.1333G>A	p.Val445Met	missense	Exon 15 of 25	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16618 AN: 152108 Hom.: 1088 Cov.: 33

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0922

Gnomad ASJ AF: 0.0848

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0344

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.0771 AC: 14664 AN: 190156 AF XY: 0.0756

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.0571

Gnomad ASJ exome AF: 0.0844

Gnomad EAS exome AF: 0.000143

Gnomad FIN exome AF: 0.0540

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.0899

GnomAD4 exome AF: 0.101 AC: 143446 AN: 1427294 Hom.: 8095 Cov.: 32 AF XY: 0.0981 AC XY: 69363 AN XY: 707190

African (AFR) AF: 0.170 AC: 5538 AN: 32482

American (AMR) AF: 0.0621 AC: 2519 AN: 40588

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 2219 AN: 25586

East Asian (EAS) AF: 0.000293 AC: 11 AN: 37492

South Asian (SAS) AF: 0.0326 AC: 2677 AN: 82144

European-Finnish (FIN) AF: 0.0581 AC: 2872 AN: 49416

Middle Eastern (MID) AF: 0.0916 AC: 525 AN: 5734

European-Non Finnish (NFE) AF: 0.111 AC: 121017 AN: 1094828

Other (OTH) AF: 0.103 AC: 6068 AN: 59024

GnomAD4 genome AF: 0.109 AC: 16641 AN: 152226 Hom.: 1094 Cov.: 33 AF XY: 0.103 AC XY: 7653 AN XY: 74440

African (AFR) AF: 0.165 AC: 6858 AN: 41524

American (AMR) AF: 0.0920 AC: 1408 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 294 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0354 AC: 171 AN: 4826

European-Finnish (FIN) AF: 0.0497 AC: 527 AN: 10606

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7068 AN: 68012

Other (OTH) AF: 0.107 AC: 225 AN: 2112

Alfa AF: 0.101 Hom.: 1427

Bravo AF: 0.118

TwinsUK AF: 0.111 AC: 413

ALSPAC AF: 0.111 AC: 427

ESP6500AA AF: 0.164 AC: 711

ESP6500EA AF: 0.104 AC: 887

ExAC AF: 0.0656 AC: 7784

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Disorder of bone (1)
-	-	1	Osteopetrosis (1)
-	-	-	Autosomal recessive osteopetrosis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Benign	0.68
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.89	L
PhyloP100		0.79
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.21
Sift	Benign	0.58	T
Sift4G	Benign	0.34	T
Polyphen		0.0050	B
Vest4		0.094
MPC		0.59
ClinPred		0.0019	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.58
Mutation Taster		=99/1	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: rs12926089; hg19: chr16-1502857; COSMIC: COSV51970417; COSMIC: COSV51970417;