rs35280276

Variant names:

• chr16-1460537-A-G
• rs35280276
• NM_001287.6:c.485-10T>C

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.485-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,601,914 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 0.13 (1472 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12795 hom.)
• Consequence: CLCN7 NM_001287.6 intron
• Scores: Splicing: ADA: 0.0003185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.167
• Publications: 8 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=-0.89).
• BP6: Variant 16-1460537-A-G is Benign according to our data. Variant chr16-1460537-A-G is described in ClinVar as Benign. ClinVar VariationId is 257956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 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.485-10T>C		intron	N/A	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.413-10T>C		intron	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.485-10T>C		intron	N/A	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.413-10T>C		intron	N/A	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.485-10T>C		intron	N/A	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20268 AN: 152068 Hom.: 1470 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.00832

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0797

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.112 AC: 27998 AN: 249376 AF XY: 0.114

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0815

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.00735

Gnomad FIN exome AF: 0.0849

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.129 AC: 186512 AN: 1449732 Hom.: 12795 Cov.: 28 AF XY: 0.128 AC XY: 92560 AN XY: 721864

African (AFR) AF: 0.173 AC: 5745 AN: 33252

American (AMR) AF: 0.0861 AC: 3848 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 4024 AN: 26068

East Asian (EAS) AF: 0.0172 AC: 683 AN: 39618

South Asian (SAS) AF: 0.112 AC: 9655 AN: 86012

European-Finnish (FIN) AF: 0.0902 AC: 4734 AN: 52488

Middle Eastern (MID) AF: 0.165 AC: 948 AN: 5750

European-Non Finnish (NFE) AF: 0.135 AC: 148702 AN: 1101858

Other (OTH) AF: 0.136 AC: 8173 AN: 59988

GnomAD4 genome AF: 0.133 AC: 20284 AN: 152182 Hom.: 1472 Cov.: 32 AF XY: 0.129 AC XY: 9570 AN XY: 74406

African (AFR) AF: 0.167 AC: 6951 AN: 41526

American (AMR) AF: 0.134 AC: 2058 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 525 AN: 3472

East Asian (EAS) AF: 0.00835 AC: 43 AN: 5152

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

European-Finnish (FIN) AF: 0.0797 AC: 846 AN: 10618

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8883 AN: 67964

Other (OTH) AF: 0.135 AC: 285 AN: 2114

Alfa AF: 0.132 Hom.: 446

Bravo AF: 0.138

Asia WGS AF: 0.0550 AC: 190 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	-0.89
CADD	Benign	8.4
DANN	Benign	0.55
PhyloP100		0.17
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
SpliceAI score (max)		0.010		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: rs35280276; hg19: chr16-1510538;