X-50070030-G-A

Position:

• chrX-50070030-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001127898.4(CLCN5):​c.315G>A​(p.Glu105=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CLCN5 NM_001127898.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.89

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-50070030-G-A is Pathogenic according to our data. Variant chrX-50070030-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2674619.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-50070030-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN5	NM_001127898.4	c.315G>A	p.Glu105=	splice_region_variant, synonymous_variant	5/15	ENST00000376091.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN5	ENST00000376091.8	c.315G>A	p.Glu105=	splice_region_variant, synonymous_variant	5/15	2	NM_001127898.4	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dent disease type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Apr 21, 2022

The c.105G>A, p.Glu35= variant in the CLCN5 gene is a synonymous variant resulting in a substitution of an adenine with a guanine at the last nucleotide of exon 2/12 of the encoded transcript [NM_000084.5]. It predicted to disrupt splicing based on in silico analyses (TraP-score, Human splicing finder, MaxEntScan and dbscSNV) and cause loss of function of the protein. This variant is absent from the gnomAD database, indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in a patient with Dent disease (PMID: 25907713). Functional studies in vitro indicate that it disrupts the original splicing donor site, resulting in the generation of an aberrant donor site that led to a 23 bp insertion and frameshift (PMID: 32201916). CLCN5 encodes a voltage-gated chloride ion channel that belongs to a distinct branch of the chloride channel family. Loss of function variants in CLCN5 have been shown to be associated with X-linked renal tubular disorders characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and renal failure (PMID: 10906159, 8559248). Female carriers displayed a milder and variable phenotype (PMID: 8559248, 25907713). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.81		Position offset: 23
DS_DL_spliceai		0.96		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-49834685;