16-1459122-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001287.6(CLCN7):c.660C>T(p.His220His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,611,256 control chromosomes in the GnomAD database, including 14,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1753 hom., cov: 34)

Exomes 𝑓: 0.13 ( 12514 hom. )

Consequence

CLCN7
NM_001287.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.80

Publications

10 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 16-1459122-G-A is Benign according to our data. Variant chr16-1459122-G-A is described in ClinVar as [Benign]. Clinvar id is 257957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.8 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN7	NM_001287.6 link	c.660C>T	p.His220His	synonymous_variant	Exon 7 of 25	ENST00000382745.9	NP_001278.1	P51798-1
CLCN7	NM_001114331.3 link	c.588C>T	p.His196His	synonymous_variant	Exon 6 of 24		NP_001107803.1	P51798-2
CLCN7	XM_011522354.2 link	c.486C>T	p.His162His	synonymous_variant	Exon 7 of 25		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9 link	c.660C>T	p.His220His	synonymous_variant	Exon 7 of 25	1	NM_001287.6	ENSP00000372193.4		P51798-1

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21581

AN:

152160

Hom.:

1753

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.00867

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0799

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.144

GnomAD2 exomes

AF:

0.113

AC:

28041

AN:

248232

AF XY:

0.114

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.0812

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.00736

Gnomad FIN exome

AF:

0.0864

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.127

AC:

184761

AN:

1458978

Hom.:

12514

Cov.:

AF XY:

0.126

AC XY:

91439

AN XY:

725426

show subpopulations

African (AFR)

AF:

0.209

AC:

6985

AN:

33444

American (AMR)

AF:

0.0860

AC:

3832

AN:

44580

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

3841

AN:

26124

East Asian (EAS)

AF:

0.0173

AC:

686

AN:

39646

South Asian (SAS)

AF:

0.112

AC:

9624

AN:

86118

European-Finnish (FIN)

AF:

0.0914

AC:

4817

AN:

52724

Middle Eastern (MID)

AF:

0.163

AC:

938

AN:

5760

European-Non Finnish (NFE)

AF:

0.131

AC:

145876

AN:

1110326

Other (OTH)

AF:

0.135

AC:

8162

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

7786

15571

23357

31142

38928

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5320

10640

15960

21280

26600

<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:

0.142

AC:

21603

AN:

152278

Hom.:

1753

Cov.:

AF XY:

0.137

AC XY:

10232

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.205

AC:

8512

AN:

41556

American (AMR)

AF:

0.136

AC:

2085

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

502

AN:

3466

East Asian (EAS)

AF:

0.00869

AC:

AN:

5178

South Asian (SAS)

AF:

0.109

AC:

524

AN:

4828

European-Finnish (FIN)

AF:

0.0799

AC:

848

AN:

10616

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.127

AC:

8653

AN:

68016

Other (OTH)

AF:

0.141

AC:

298

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

968

1936

2903

3871

4839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.119

Hom.:

549

Bravo

AF:

0.148

Asia WGS

AF:

0.0540

AC:

189

AN:

3478

EpiCase

AF:

0.137

EpiControl

AF:

0.139

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 13, 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

-0.59

CADD

Benign

2.0

(source)

DANN

Benign

0.95

PhyloP100

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=92/8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over