16-1454436-C-T

Position:

chr16-1454436-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001287.6(CLCN7):c.1128G>A(p.Pro376=) 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

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 -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 id is 257948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1454436-C-T is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CLCN7	NM_001287.6 linkuse as main transcript	c.1128G>A	p.Pro376=	synonymous_variant	13/25	ENST00000382745.9	NP_001278.1
CLCN7	NM_001114331.3 linkuse as main transcript	c.1056G>A	p.Pro352=	synonymous_variant	12/24		NP_001107803.1
CLCN7	XM_011522354.2 linkuse as main transcript	c.954G>A	p.Pro318=	synonymous_variant	13/25		XP_011520656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN7	ENST00000382745.9 linkuse as main transcript	c.1128G>A	p.Pro376=	synonymous_variant	13/25	1	NM_001287.6	ENSP00000372193	P1	P51798-1

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

GnomAD3 exomes

AF:

0.0663

AC:

16617

AN:

250802

Hom.:

697

AF XY:

0.0672

AC XY:

9123

AN XY:

135824

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 SAS exome

AF:

0.0312

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

Gnomad4 AFR exome

AF:

0.0263

Gnomad4 AMR exome

AF:

0.0506

Gnomad4 ASJ exome

AF:

0.0867

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0318

Gnomad4 FIN exome

AF:

0.0573

Gnomad4 NFE exome

AF:

0.107

Gnomad4 OTH exome

AF:

0.0905

GnomAD4 genome

AF:

0.0676

AC:

10296

AN:

152298

Hom.:

446

Cov.:

AF XY:

0.0631

AC XY:

4695

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0282

Gnomad4 AMR

AF:

0.0741

Gnomad4 ASJ

AF:

0.0836

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0339

Gnomad4 FIN

AF:

0.0488

Gnomad4 NFE

AF:

0.0996

Gnomad4 OTH

AF:

0.0743

Alfa

AF:

0.0797

Hom.:

384

Bravo

AF:

0.0698

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.109

EpiControl

AF:

0.104

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Osteopetrosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

-0.34

CADD

Benign

1.2

DANN

Benign

0.91

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