16-1454436-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001287.6(CLCN7):c.1128G>A(p.Pro376Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,613,388 control chromosomes in the GnomAD database, including 7,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 446 hom., cov: 34)

Exomes 𝑓: 0.093 ( 7222 hom. )

Consequence

CLCN7
NM_001287.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.360

Publications

11 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 16-1454436-C-T is Benign according to our data. Variant chr16-1454436-C-T is described in ClinVar as Benign. ClinVar VariationId is 257948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.36 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0976 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN7	NM_001287.6	MANE Select	c.1128G>A	p.Pro376Pro	synonymous	Exon 13 of 25	NP_001278.1
	CLCN7	NM_001114331.3		c.1056G>A	p.Pro352Pro	synonymous	Exon 12 of 24	NP_001107803.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCN7	ENST00000382745.9	TSL:1 MANE Select	c.1128G>A	p.Pro376Pro	synonymous	Exon 13 of 25	ENSP00000372193.4
CLCN7	ENST00000262318.12	TSL:5	c.1056G>A	p.Pro352Pro	synonymous	Exon 12 of 24	ENSP00000262318.8
CLCN7	ENST00000699947.1		c.1128G>A	p.Pro376Pro	synonymous	Exon 13 of 25	ENSP00000514703.1

Frequencies

GnomAD3 genomes

AF:

0.0677

AC:

10301

AN:

152180

Hom.:

446

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0283

Gnomad AMI

AF:

0.0758

Gnomad AMR

AF:

0.0743

Gnomad ASJ

AF:

0.0836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0329

Gnomad FIN

AF:

0.0488

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0996

Gnomad OTH

AF:

0.0761

GnomAD2 exomes

AF:

0.0663

AC:

16617

AN:

250802

AF XY:

0.0672

show subpopulations

Gnomad AFR exome

AF:

0.0262

Gnomad AMR exome

AF:

0.0469

Gnomad ASJ exome

AF:

0.0842

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0537

Gnomad NFE exome

AF:

0.0982

Gnomad OTH exome

AF:

0.0788

GnomAD4 exome

AF:

0.0932

AC:

136117

AN:

1461090

Hom.:

7222

Cov.:

AF XY:

0.0913

AC XY:

66376

AN XY:

726836

show subpopulations

African (AFR)

AF:

0.0263

AC:

881

AN:

33474

American (AMR)

AF:

0.0506

AC:

2263

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0867

AC:

2265

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39698

South Asian (SAS)

AF:

0.0318

AC:

2746

AN:

86256

European-Finnish (FIN)

AF:

0.0573

AC:

3035

AN:

52950

Middle Eastern (MID)

AF:

0.0817

AC:

470

AN:

5754

European-Non Finnish (NFE)

AF:

0.107

AC:

118983

AN:

1111724

Other (OTH)

AF:

0.0905

AC:

5467

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

6614

13227

19841

26454

33068

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4310

8620

12930

17240

21550

<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:

0.0676

AC:

10296

AN:

152298

Hom.:

446

Cov.:

AF XY:

0.0631

AC XY:

4695

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0282

AC:

1171

AN:

41578

American (AMR)

AF:

0.0741

AC:

1134

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0836

AC:

290

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0339

AC:

164

AN:

4832

European-Finnish (FIN)

AF:

0.0488

AC:

518

AN:

10620

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0996

AC:

6773

AN:

68012

Other (OTH)

AF:

0.0743

AC:

157

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

497

994

1492

1989

2486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0806

Hom.:

432

Bravo

AF:

0.0698

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.109

EpiControl

AF:

0.104

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

1.2

(source)

DANN

Benign

0.91

PhyloP100

-0.36

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over