rs797044814

Positions:

• chrX-50092130-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001127898.4(CLCN5):​c.2362C>T​(p.Arg788Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CLCN5 NM_001127898.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.05692
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.29

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0363 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-50092130-C-T is Pathogenic according to our data. Variant chrX-50092130-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 208000.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-50092130-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN5	NM_001127898.4	c.2362C>T	p.Arg788Ter	stop_gained, splice_region_variant	15/15	ENST00000376091.8	NP_001121370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN5	ENST00000376091.8	c.2362C>T	p.Arg788Ter	stop_gained, splice_region_variant	15/15	2	NM_001127898.4	ENSP00000365259	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1079529 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 347577

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dent disease type 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Apr 17, 2018	This individual is hemizygous for a known nonsense variant, c.2362C>T, in the CLCN5 gene. This variant creates a premature stop codon (p.Arg788*). c.2362C>T (p.Arg788*) has not been listed in any population databases (i.e. ExAC, ESP or dbSNP). The variant has been reported in five unrelated patients with Dent's disease (Carballo-Trujillo et.al. Nephrol Dial Transplant 2003; 18(4): 717-723, Hoopes et.al. Kidney Int 2004; 65: 1615-1620, Wu et.al. Nephron Physiol 2009; 112: 53-62 & Grand et.al. Kidney Int 2009; 76: 999-1005). Segregation studies were performed by Carballo-Trujillo et.al and c.2362C>T was shown to cosegregate with the disease. In these reports, the variant is described as p.Arg718* (relative to transcript NM_000084.4). Functional studies in Xenopus laevis oocytes showed that this nonsense variant produced a truncated protein product and was lower in abundance in comparison to the wild-type. The truncation affected the cellular localisation of the protein (Grand et.al. Kidney Int 2009; 76: 999-1005). This variant is considered to be pathogenic according to the ACMG guidelines. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

This sequence change creates a premature translational stop signal (p.Arg718*) in the CLCN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the CLCN5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Dent disease (PMID: 12637640, 31672324). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208000). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLCN5 function (PMID: 19657328). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	D;D;D;D
Vest4		0.54
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.057
dbscSNV1_RF	Benign	0.48
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

Other links and lift over

dbSNP: rs797044814; hg19: chrX-49856787; COSMIC: COSV56585339;