chr16-1448774-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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:5

Conservation

PhyloP100: -0.557

Publications

8 publications found

Variant links:

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

CLCN7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLCN7	NM_001287.6 link	c.1798-8G>A	splice_region_variant, intron_variant	Intron 19 of 24	ENST00000382745.9	NP_001278.1	P51798-1
CLCN7	NM_001114331.3 link	c.1726-8G>A	splice_region_variant, intron_variant	Intron 18 of 23		NP_001107803.1	P51798-2
CLCN7	XM_011522354.2 link	c.1624-8G>A	splice_region_variant, 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 link	c.1798-8G>A		splice_region_variant, intron_variant	Intron 19 of 24	1	NM_001287.6	ENSP00000372193.4		P51798-1

Frequencies

GnomAD3 genomes

AF:

0.0997

AC:

15156

AN:

152022

Hom.:

840

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0985

AC XY:

71460

AN XY:

725146

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

6942

13885

20827

27770

34712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4538

9076

13614

18152

22690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0997

AC:

15174

AN:

152140

Hom.:

843

Cov.:

AF XY:

0.0936

AC XY:

6959

AN XY:

74382

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.105

AC:

7160

AN:

67960

Other (OTH)

AF:

0.106

AC:

223

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

685

1369

2054

2738

3423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.109

Hom.:

504

Bravo

AF:

0.107

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Osteopetrosis

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.49

(source)

DANN

Benign

0.79

PhyloP100

-0.56

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over