rs797044810

chrX-50086562-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.1249C>T(p.Arg417Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000911 in 1,097,964 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R417R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CLCN5 NM_001127898.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 3.93

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-50086562-C-T is Pathogenic according to our data. Variant chrX-50086562-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 207996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-50086562-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN5	NM_001127898.4	c.1249C>T	p.Arg417Ter	stop_gained	11/15	ENST00000376091.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN5	ENST00000376091.8	c.1249C>T	p.Arg417Ter	stop_gained	11/15	2	NM_001127898.4	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097964 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363332

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dent disease type 1 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	Mar 07, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 15, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 11 of 15). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (ClinVar; Decipher). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with Dent disease (PMID: 24081861, ClinVar, LOVD). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 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 at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9328929, 24081861, 25907713, 31674016, 25525159, 32683654, 15814539) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 15, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 207996). This premature translational stop signal has been observed in individual(s) with Dent disease (PMID: 31672324, 31674016). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg347*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	37
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.92
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs797044810; hg19: chrX-49851219; COSMIC: COSV56582168;