16-1448950-C-T

Variant names:

• chr16-1448950-C-T
• rs12932780
• NM_001287.6:c.1797+16G>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.1797+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0949 in 1,611,712 control chromosomes in the GnomAD database, including 8,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (727 hom., cov: 33)
  • Exomes 𝑓: 0.095 (7390 hom.)
• Consequence: CLCN7 NM_001287.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.254
• Publications: 10 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• autosomal recessive osteopetrosis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp, Ambry Genetics
• hypopigmentation, organomegaly, and delayed myelination and development

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), 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 16-1448950-C-T is Benign according to our data. Variant chr16-1448950-C-T is described in ClinVar as [Benign]. Clinvar id is 257952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN7	NM_001287.6	c.1797+16G>A		intron_variant	Intron 19 of 24	ENST00000382745.9	NP_001278.1
CLCN7	NM_001114331.3	c.1725+16G>A		intron_variant	Intron 18 of 23		NP_001107803.1
CLCN7	XM_011522354.2	c.1623+16G>A		intron_variant	Intron 19 of 24		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9	c.1797+16G>A		intron_variant	Intron 19 of 24	1	NM_001287.6	ENSP00000372193.4

Frequencies

GnomAD3 genomes AF: 0.0915 AC: 13908 AN: 152072 Hom.: 726 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0942

GnomAD2 exomes AF: 0.0715 AC: 17758 AN: 248500 AF XY: 0.0710

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0513

Gnomad ASJ exome AF: 0.0581

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0541

Gnomad NFE exome AF: 0.0986

Gnomad OTH exome AF: 0.0814

GnomAD4 exome AF: 0.0952 AC: 138971 AN: 1459522 Hom.: 7390 Cov.: 35 AF XY: 0.0930 AC XY: 67553 AN XY: 726080

African (AFR) AF: 0.115 AC: 3859 AN: 33476

American (AMR) AF: 0.0561 AC: 2509 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 1568 AN: 26134

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0323 AC: 2785 AN: 86252

European-Finnish (FIN) AF: 0.0577 AC: 2958 AN: 51242

Middle Eastern (MID) AF: 0.0894 AC: 515 AN: 5762

European-Non Finnish (NFE) AF: 0.107 AC: 119128 AN: 1111874

Other (OTH) AF: 0.0935 AC: 5642 AN: 60368

GnomAD4 genome AF: 0.0914 AC: 13916 AN: 152190 Hom.: 727 Cov.: 33 AF XY: 0.0857 AC XY: 6375 AN XY: 74416

African (AFR) AF: 0.112 AC: 4658 AN: 41522

American (AMR) AF: 0.0841 AC: 1286 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0353 AC: 170 AN: 4820

European-Finnish (FIN) AF: 0.0483 AC: 513 AN: 10618

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6796 AN: 67976

Other (OTH) AF: 0.0922 AC: 195 AN: 2114

Alfa AF: 0.0938 Hom.: 996

Bravo AF: 0.0971

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.19
DANN	Benign	0.62
PhyloP100		-0.25
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: rs12932780; hg19: chr16-1498951;