rs114827619

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001287.6(CLCN7):c.1961C>T(p.Thr654Met) variant causes a missense change. The variant allele was found at a frequency of 0.000854 in 1,612,678 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T654T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0045 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00047 ( 6 hom. )

Consequence

CLCN7
NM_001287.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.55

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006703049).

BP6

Variant 16-1448407-G-A is Benign according to our data. Variant chr16-1448407-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1448407-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00452 (689/152324) while in subpopulation AFR AF= 0.0156 (650/41570). AF 95% confidence interval is 0.0146. There are 2 homozygotes in gnomad4. There are 322 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CLCN7	NM_001287.6 linkuse as main transcript	c.1961C>T	p.Thr654Met	missense_variant	21/25	ENST00000382745.9
CLCN7	NM_001114331.3 linkuse as main transcript	c.1889C>T	p.Thr630Met	missense_variant	20/24
CLCN7	XM_011522354.2 linkuse as main transcript	c.1787C>T	p.Thr596Met	missense_variant	21/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN7	ENST00000382745.9 linkuse as main transcript	c.1961C>T	p.Thr654Met	missense_variant	21/25	1	NM_001287.6	P1	P51798-1

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

686

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00117

AC:

292

AN:

249498

Hom.:

AF XY:

0.000864

AC XY:

117

AN XY:

135472

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.000840

Gnomad ASJ exome

AF:

0.000900

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000800

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.000471

AC:

688

AN:

1460354

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

293

AN XY:

726458

show subpopulations

Gnomad4 AFR exome

AF:

0.0151

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.00452

AC:

689

AN:

152324

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0156

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000885

Hom.:

Bravo

AF:

0.00512

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00143

AC:

173

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2015	- -

Osteopetrosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

D;D;D

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Pathogenic

3.3

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.6

N;N;N

REVEL

Uncertain

0.54

Sift

Benign

0.035

D;D;D

Sift4G

Benign

0.072

T;T;D

Polyphen

0.95

P;.;.

Vest4

0.58

MVP

0.86

MPC

0.73

ClinPred

0.046

GERP RS

4.2

Varity_R

0.058

gMVP

0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over