NM_001287.6:c.-204G>A

Variant names:

• chr16-1475178-C-T
• rs960467
• NM_001287.6:c.-204G>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.-204G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 343,084 control chromosomes in the GnomAD database, including 11,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4215 hom., cov: 32)
  • Exomes 𝑓: 0.25 (7189 hom.)
• Consequence: CLCN7 NM_001287.6 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.312
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-1475178-C-T is Benign according to our data. Variant chr16-1475178-C-T is described in ClinVar as Benign. ClinVar VariationId is 1232538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 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.-204G>A		upstream_gene	N/A	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.-204G>A		upstream_gene	N/A	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.-204G>A		upstream_gene	N/A	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.-204G>A		upstream_gene	N/A	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.-204G>A		upstream_gene	N/A	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34431 AN: 151556 Hom.: 4213 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.226

GnomAD4 exome AF: 0.255 AC: 48788 AN: 191420 Hom.: 7189 Cov.: 4 AF XY: 0.252 AC XY: 25249 AN XY: 100130

African (AFR) AF: 0.189 AC: 750 AN: 3962

American (AMR) AF: 0.251 AC: 1078 AN: 4294

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 1295 AN: 5998

East Asian (EAS) AF: 0.566 AC: 8536 AN: 15090

South Asian (SAS) AF: 0.238 AC: 2449 AN: 10296

European-Finnish (FIN) AF: 0.269 AC: 4531 AN: 16862

Middle Eastern (MID) AF: 0.224 AC: 184 AN: 820

European-Non Finnish (NFE) AF: 0.222 AC: 27231 AN: 122712

Other (OTH) AF: 0.240 AC: 2734 AN: 11386

GnomAD4 genome AF: 0.227 AC: 34447 AN: 151664 Hom.: 4215 Cov.: 32 AF XY: 0.232 AC XY: 17237 AN XY: 74142

African (AFR) AF: 0.176 AC: 7273 AN: 41418

American (AMR) AF: 0.249 AC: 3802 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 788 AN: 3468

East Asian (EAS) AF: 0.521 AC: 2643 AN: 5074

South Asian (SAS) AF: 0.273 AC: 1315 AN: 4820

European-Finnish (FIN) AF: 0.260 AC: 2736 AN: 10540

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.223 AC: 15089 AN: 67782

Other (OTH) AF: 0.226 AC: 475 AN: 2106

Alfa AF: 0.210 Hom.: 442

Bravo AF: 0.223

Asia WGS AF: 0.389 AC: 1346 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.86
PhyloP100		0.31
PromoterAI		0.029	Neutral
Mutation Taster		=300/0	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: rs960467; hg19: chr16-1525179;