rs151340628

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001127898.4(CLCN5):​c.1049G>A​(p.Arg350His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,612 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

CLCN5
NM_001127898.4 missense

Scores

15
1
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.89
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLCN5NM_001127898.4 linkuse as main transcriptc.1049G>A p.Arg350His missense_variant 11/15 ENST00000376091.8 NP_001121370.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLCN5ENST00000376091.8 linkuse as main transcriptc.1049G>A p.Arg350His missense_variant 11/152 NM_001127898.4 ENSP00000365259 P3P51795-2

Frequencies

GnomAD3 genomes
AF:
0.00000897
AC:
1
AN:
111503
Hom.:
0
Cov.:
22
AF XY:
0.0000297
AC XY:
1
AN XY:
33705
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000111
AC:
2
AN:
180156
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
64950
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000125
Gnomad OTH exome
AF:
0.000224
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1097109
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
362559
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
AF:
0.00000897
AC:
1
AN:
111503
Hom.:
0
Cov.:
22
AF XY:
0.0000297
AC XY:
1
AN XY:
33705
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.66
D
BayesDel_noAF
Pathogenic
0.71
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
.;.;D;D;D;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
.;D;.;.;D;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
.;.;H;H;H;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-4.8
D;D;D;.;D;.
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;D;.;D;.
Sift4G
Uncertain
0.035
D;D;D;.;D;.
Polyphen
0.98
D;D;D;D;D;.
Vest4
0.84
MutPred
0.88
.;.;Gain of ubiquitination at K276 (P = 0.0486);Gain of ubiquitination at K276 (P = 0.0486);Gain of ubiquitination at K276 (P = 0.0486);.;
MVP
1.0
MPC
1.4
ClinPred
0.99
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs151340628; hg19: chrX-49851019; COSMIC: COSV56582155; API