rs35915213

Variant names:

• chr16-1448774-C-T
• rs35915213
• NM_001287.6:c.1798-8G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-1448774-C-T
• chr16-1448774-C-A
• chr16-1448774-C-G

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.1798-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,609,752 control chromosomes in the GnomAD database, including 9,054 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (843 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8211 hom.)
• Consequence: CLCN7 NM_001287.6 splice_region, intron
• Scores: Splicing: ADA: 0.00006909
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.557
• 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=-0.85).
• BP6: Variant 16-1448774-C-T is Benign according to our data. Variant chr16-1448774-C-T is described in ClinVar as Benign. ClinVar VariationId is 257954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 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.1798-8G>A		splice_region intron	N/A	NP_001278.1	P51798-1
	CLCN7	NM_001114331.3		c.1726-8G>A		splice_region 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.1798-8G>A		splice_region intron	N/A	ENSP00000372193.4	P51798-1
	CLCN7	ENST00000262318.12	TSL:5	c.1726-8G>A		splice_region intron	N/A	ENSP00000262318.8	H0Y2M6
	CLCN7	ENST00000892994.1		c.1879-8G>A		splice_region intron	N/A	ENSP00000563053.1

Frequencies

GnomAD3 genomes AF: 0.0997 AC: 15156 AN: 152022 Hom.: 840 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0941

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.0777 AC: 19215 AN: 247232 AF XY: 0.0770

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.0576

Gnomad ASJ exome AF: 0.0917

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0550

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.0904

GnomAD4 exome AF: 0.101 AC: 146830 AN: 1457612 Hom.: 8211 Cov.: 35 AF XY: 0.0985 AC XY: 71460 AN XY: 725146

African (AFR) AF: 0.131 AC: 4372 AN: 33454

American (AMR) AF: 0.0629 AC: 2813 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0940 AC: 2456 AN: 26122

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39692

South Asian (SAS) AF: 0.0346 AC: 2983 AN: 86236

European-Finnish (FIN) AF: 0.0582 AC: 2926 AN: 50302

Middle Eastern (MID) AF: 0.106 AC: 583 AN: 5496

European-Non Finnish (NFE) AF: 0.112 AC: 124551 AN: 1111308

Other (OTH) AF: 0.102 AC: 6139 AN: 60288

GnomAD4 genome AF: 0.0997 AC: 15174 AN: 152140 Hom.: 843 Cov.: 33 AF XY: 0.0936 AC XY: 6959 AN XY: 74382

African (AFR) AF: 0.126 AC: 5238 AN: 41502

American (AMR) AF: 0.0939 AC: 1435 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 328 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0379 AC: 183 AN: 4834

European-Finnish (FIN) AF: 0.0483 AC: 512 AN: 10600

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7160 AN: 67960

Other (OTH) AF: 0.106 AC: 223 AN: 2110

Alfa AF: 0.109 Hom.: 504

Bravo AF: 0.107

Asia WGS AF: 0.0220 AC: 78 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	-0.85
CADD	Benign	0.49
DANN	Benign	0.79
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.0020
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: rs35915213; hg19: chr16-1498775; COSMIC: COSV99060052; COSMIC: COSV99060052;