rs2235580

Variant names:

• chr16-1465161-C-T
• rs2235580
• NM_001287.6:c.213+106G>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.213+106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,082,180 control chromosomes in the GnomAD database, including 107,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13649 hom., cov: 33)
  • Exomes 𝑓: 0.45 (94007 hom.)
• Consequence: CLCN7 NM_001287.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.857
• 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=-0.9).
• BP6: Variant 16-1465161-C-T is Benign according to our data. Variant chr16-1465161-C-T is described in ClinVar as Benign. ClinVar VariationId is 1283737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.467 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.213+106G>A		intron	N/A	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.142-3487G>A		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.213+106G>A		intron	N/A	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.142-3487G>A		intron	N/A	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.213+106G>A		intron	N/A	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62788 AN: 151968 Hom.: 13648 Cov.: 33

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.425

GnomAD4 exome AF: 0.446 AC: 414927 AN: 930094 Hom.: 94007 AF XY: 0.447 AC XY: 213853 AN XY: 478474

African (AFR) AF: 0.298 AC: 6794 AN: 22796

American (AMR) AF: 0.421 AC: 15223 AN: 36136

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 10672 AN: 22270

East Asian (EAS) AF: 0.274 AC: 9496 AN: 34596

South Asian (SAS) AF: 0.430 AC: 30574 AN: 71168

European-Finnish (FIN) AF: 0.483 AC: 23299 AN: 48288

Middle Eastern (MID) AF: 0.385 AC: 1254 AN: 3258

European-Non Finnish (NFE) AF: 0.461 AC: 299395 AN: 648876

Other (OTH) AF: 0.427 AC: 18220 AN: 42706

GnomAD4 genome AF: 0.413 AC: 62808 AN: 152086 Hom.: 13649 Cov.: 33 AF XY: 0.415 AC XY: 30816 AN XY: 74342

African (AFR) AF: 0.306 AC: 12677 AN: 41488

American (AMR) AF: 0.428 AC: 6543 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1587 AN: 3466

East Asian (EAS) AF: 0.274 AC: 1413 AN: 5156

South Asian (SAS) AF: 0.417 AC: 2014 AN: 4824

European-Finnish (FIN) AF: 0.492 AC: 5202 AN: 10568

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32018 AN: 67978

Other (OTH) AF: 0.427 AC: 902 AN: 2112

Alfa AF: 0.461 Hom.: 7314

Bravo AF: 0.400

Asia WGS AF: 0.351 AC: 1224 AN: 3478

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	-0.90
CADD	Benign	0.47
DANN	Benign	0.42
PhyloP100		-0.86
Mutation Taster		=100/0	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: rs2235580; hg19: chr16-1515162;