rs151340625

chrX-50088867-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001127898.4(CLCN5):c.1727G>A(p.Gly576Glu) variant causes a missense change involving the alteration of a 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G576R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: CLCN5 NM_001127898.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.78

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 11 ACMG points.

• PM1: In a intramembrane_region Helical (size 14) in uniprot entity CLCN5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001127898.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-50088866-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2822984.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-50088867-G-A is Pathogenic according to our data. Variant chrX-50088867-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11801.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN5	NM_001127898.4	c.1727G>A	p.Gly576Glu	missense_variant	12/15	ENST00000376091.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN5	ENST00000376091.8	c.1727G>A	p.Gly576Glu	missense_variant	12/15	2	NM_001127898.4	P3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked recessive nephrolithiasis with renal failure Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1996

- -

Dent disease type 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
Cadd	Pathogenic	30
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.9	D;D;D;.;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;.;D;.
Polyphen		1.0	D;D;D;D;D;.
Vest4		1.0
MutPred		0.95		.;.;Loss of catalytic residue at A507 (P = 0.0659);Loss of catalytic residue at A507 (P = 0.0659);Loss of catalytic residue at A507 (P = 0.0659);.;
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		1.0

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: rs151340625; hg19: chrX-49853524;