Genetic Variant CLCN5:p.Trp349* (chrX-50086359-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001127898.4(CLCN5):c.1046G>A(p.Trp349*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,097,084 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CLCN5
NM_001127898.4 stop_gained

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 9.89

Publications

1 publications found

Variant links:

Genes affected

CLCN5 (HGNC:2023): (chloride voltage-gated channel 5) This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

CLCN5 Gene-Disease associations (from GenCC):

Dent disease type 1
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

CLCN5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCN5	NM_001127898.4	MANE Select	c.1046G>A	p.Trp349*	stop_gained	Exon 11 of 15	NP_001121370.1
CLCN5	NM_001440756.1		c.1058G>A	p.Trp353*	stop_gained	Exon 11 of 15	NP_001427685.1
CLCN5	NM_001440757.1		c.1058G>A	p.Trp353*	stop_gained	Exon 11 of 15	NP_001427686.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.1046G>A	p.Trp349*	stop_gained	Exon 11 of 15	ENSP00000365259.3
CLCN5	ENST00000307367.2	TSL:1	c.836G>A	p.Trp279*	stop_gained	Exon 8 of 12	ENSP00000304257.2
CLCN5	ENST00000376108.7	TSL:1	c.836G>A	p.Trp279*	stop_gained	Exon 8 of 12	ENSP00000365276.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1097084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26386

American (AMR)

AF:

0.00

AC:

AN:

35117

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.00

AC:

AN:

30184

South Asian (SAS)

AF:

0.00

AC:

AN:

53962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40449

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841433

Other (OTH)

AF:

0.0000217

AC:

AN:

46051

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

Dent disease type 1

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.9

Vest4

0.89

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over