rs151340626

Variant names:

• chrX-50085987-C-A
• rs151340626
• NM_001127898.4:c.941C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-50085987-C-A
• chrX-50085987-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001127898.4(CLCN5):​c.941C>A​(p.Ser314*) variant causes a stop gained 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S314S) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CLCN5 NM_001127898.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.82
• Publications: 26 publications found

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]

CLCN5 Gene-Disease associations (from GenCC):

• Dent disease type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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-50085987-C-A is Pathogenic according to our data. Variant chrX-50085987-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1029478.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	NM_001127898.4	MANE Select	c.941C>A	p.Ser314*	stop_gained	Exon 10 of 15	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.953C>A	p.Ser318*	stop_gained	Exon 10 of 15	NP_001427685.1
	CLCN5	NM_001440757.1		c.953C>A	p.Ser318*	stop_gained	Exon 10 of 15	NP_001427686.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.941C>A	p.Ser314*	stop_gained	Exon 10 of 15	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000307367.2	TSL:1	c.731C>A	p.Ser244*	stop_gained	Exon 7 of 12	ENSP00000304257.2	P51795-1
	CLCN5	ENST00000376108.7	TSL:1	c.731C>A	p.Ser244*	stop_gained	Exon 7 of 12	ENSP00000365276.3	P51795-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1093244 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 359026

African (AFR) AF: 0.00 AC: 0 AN: 26288

American (AMR) AF: 0.00 AC: 0 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.00 AC: 0 AN: 54019

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837674

Other (OTH) AF: 0.00 AC: 0 AN: 45964

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Dent disease type 1 (1)
1	-	-	Hypophosphatemic rickets, X-linked recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.8
Vest4		0.84
GERP RS		6.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs151340626; hg19: chrX-49850644;