X-50070007-C-T

Position:

• chrX-50070007-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001127898.4(CLCN5):​c.292C>T​(p.Arg98Ter) variant causes a stop gained 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CLCN5 NM_001127898.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.94

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 Pathogenic. Variant got 18 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
• PP5: Variant X-50070007-C-T is Pathogenic according to our data. Variant chrX-50070007-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50070007-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-50070007-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.292C>T	p.Arg98Ter	stop_gained	5/15	ENST00000376091.8	NP_001121370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN5	ENST00000376091.8	c.292C>T	p.Arg98Ter	stop_gained	5/15	2	NM_001127898.4	ENSP00000365259	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12631345, 29391272, 25525159, 9734595, 16807762, 15125028, 26308078, 27174143, 24810952, 22350370, 28815356, 31672324) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 07, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 488682). This premature translational stop signal has been observed in individual(s) with Dent disease (PMID: 9734595, 24081861, 25907713). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg28*) in the CLCN5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN5 are known to be pathogenic (PMID: 22876375, 25907713). -

Dent disease type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 25, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

X-linked recessive nephrolithiasis with renal failure;C1839874:Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;C1845168:Hypophosphatemic rickets, X-linked recessive;C1848336:Dent disease type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.79
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1049618423; hg19: chrX-49834662;