X-49925299-A-G

Position:

• chrX-49925299-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001127898.4(CLCN5):​c.1A>G​(p.Met1?) variant causes a start lost change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: CLCN5 NM_001127898.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73

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 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN5	NM_001127898.4	c.1A>G	p.Met1?	start_lost	3/15	ENST00000376091.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN5	ENST00000376091.8	c.1A>G	p.Met1?	start_lost	3/15	2	NM_001127898.4	P3
CLCN5	ENST00000376088.7	c.1A>G	p.Met1?	start_lost	3/15	2		P3
CLCN5	ENST00000482218.2	c.1A>G	p.Met1?	start_lost	2/3	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dent disease type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Dent disease (MIM#300009), hypophosphatemic rickets (MIM#300554), nephrolithiasis type I (MIM#310468) and low molecular weight proteinuria with hypercalciuria and nephrocalcinosis (MIM#308990). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity, with intra- and inter-familial phenotypic variability previously reported (PMID: 28580211, OMIM). (I) 0207 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG) however, CLCN5 has alternative 5’UTR exons which results in multiple transcripts and isoforms with alternative start sites (PMID: 25001568). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 0705 - No other start-loss variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.72	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	-0.053	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-0.030	N;N;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;.
Polyphen		0.011	B;B;.
Vest4		0.86
MutPred		0.73		Gain of catalytic residue at M1 (P = 0.0438);Gain of catalytic residue at M1 (P = 0.0438);Gain of catalytic residue at M1 (P = 0.0438);
MVP		0.95
ClinPred		0.92	D
GERP RS		3.9
gMVP		0.36

Splicing

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-49689909;