Genetic Variant CLCN7:c.1797+16G>A (chr16-1448950-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001287.6(CLCN7):c.1797+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0949 in 1,611,712 control chromosomes in the GnomAD database, including 8,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 727 hom., cov: 33)

Exomes 𝑓: 0.095 ( 7390 hom. )

Consequence

CLCN7
NM_001287.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.254

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 16-1448950-C-T is Benign according to our data. Variant chr16-1448950-C-T is described in ClinVar as [Benign]. Clinvar id is 257952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1448950-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLCN7	NM_001287.6 link	c.1797+16G>A	intron_variant	Intron 19 of 24	ENST00000382745.9	NP_001278.1	P51798-1
CLCN7	NM_001114331.3 link	c.1725+16G>A	intron_variant	Intron 18 of 23		NP_001107803.1	P51798-2
CLCN7	XM_011522354.2 link	c.1623+16G>A	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.1797+16G>A		intron_variant	Intron 19 of 24	1	NM_001287.6	ENSP00000372193.4		P51798-1

Frequencies

GnomAD3 genomes

AF:

0.0915

AC:

13908

AN:

152072

Hom.:

726

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.0758

Gnomad AMR

AF:

0.0843

Gnomad ASJ

AF:

0.0597

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0342

Gnomad FIN

AF:

0.0483

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.100

Gnomad OTH

AF:

0.0942

GnomAD3 exomes

AF:

0.0715

AC:

17758

AN:

248500

Hom.:

770

AF XY:

0.0710

AC XY:

9588

AN XY:

135022

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.0513

Gnomad ASJ exome

AF:

0.0581

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.0316

Gnomad FIN exome

AF:

0.0541

Gnomad NFE exome

AF:

0.0986

Gnomad OTH exome

AF:

0.0814

GnomAD4 exome

AF:

0.0952

AC:

138971

AN:

1459522

Hom.:

7390

Cov.:

AF XY:

0.0930

AC XY:

67553

AN XY:

726080

show subpopulations

Gnomad4 AFR exome

AF:

0.115

Gnomad4 AMR exome

AF:

0.0561

Gnomad4 ASJ exome

AF:

0.0600

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0323

Gnomad4 FIN exome

AF:

0.0577

Gnomad4 NFE exome

AF:

0.107

Gnomad4 OTH exome

AF:

0.0935

GnomAD4 genome

AF:

0.0914

AC:

13916

AN:

152190

Hom.:

727

Cov.:

AF XY:

0.0857

AC XY:

6375

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.112

Gnomad4 AMR

AF:

0.0841

Gnomad4 ASJ

AF:

0.0597

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0353

Gnomad4 FIN

AF:

0.0483

Gnomad4 NFE

AF:

0.100

Gnomad4 OTH

AF:

0.0922

Alfa

AF:

0.0922

Hom.:

750

Bravo

AF:

0.0971

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 18, 2021

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.19

DANN

Benign

0.62

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