rs1318459336

Variant names:

• chrX-50042451-G-A
• rs1318459336
• NM_001127898.4:c.152G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-50042451-G-A
• chrX-50042451-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001127898.4(CLCN5):​c.152G>A​(p.Arg51Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000139 in 937,877 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000014 (0 hom. 4 hem.)
• Consequence: CLCN5 NM_001127898.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:4
• Conservation: PhyloP100: 5.70
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19400758).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

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.152G>A	p.Arg51Gln	missense	Exon 4 of 15	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.152G>A	p.Arg51Gln	missense	Exon 4 of 15	NP_001427685.1
	CLCN5	NM_001440757.1		c.152G>A	p.Arg51Gln	missense	Exon 4 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.152G>A	p.Arg51Gln	missense	Exon 4 of 15	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000376088.7	TSL:2	c.152G>A	p.Arg51Gln	missense	Exon 4 of 15	ENSP00000365256.3	P51795-2
	CLCN5	ENST00000854414.1		c.152G>A	p.Arg51Gln	missense	Exon 4 of 13	ENSP00000524473.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000127 AC: 1 AN: 79044 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000311

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 13 AN: 937877 Hom.: 0 Cov.: 18 AF XY: 0.0000151 AC XY: 4 AN XY: 265533

African (AFR) AF: 0.00 AC: 0 AN: 21520

American (AMR) AF: 0.00 AC: 0 AN: 21718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16294

East Asian (EAS) AF: 0.00 AC: 0 AN: 24680

South Asian (SAS) AF: 0.00 AC: 0 AN: 32233

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3717

European-Non Finnish (NFE) AF: 0.0000148 AC: 11 AN: 742965

Other (OTH) AF: 0.0000506 AC: 2 AN: 39526

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Dent disease type 1 (1)
-	1	-	Hypophosphatemic rickets, X-linked recessive (1)
-	1	-	Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis (1)
-	1	-	X-linked recessive nephrolithiasis with renal failure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.47	T
PhyloP100		5.7
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.35
Sift	Benign	0.23	T
Sift4G	Benign	0.55	T
Polyphen		0.94	P
Vest4		0.21
MutPred		0.28		Loss of solvent accessibility (P = 0.0442)
MVP		0.74
MPC		0.78
ClinPred		0.53	D
GERP RS		3.4
gMVP		0.37
Mutation Taster		=69/31	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1318459336; hg19: chrX-49807060; COSMIC: COSV65802630;