rs151340624
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_001127898.4(CLCN5):c.2320C>T(p.Arg774*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000273 in 1,097,831 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )
Consequence
CLCN5
NM_001127898.4 stop_gained
NM_001127898.4 stop_gained
Scores
2
2
Clinical Significance
Conservation
PhyloP100: 3.90
Publications
8 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 1Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0534 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-50090846-C-T is Pathogenic according to our data. Variant chrX-50090846-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11800.
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 | MANE Select | c.2320C>T | p.Arg774* | stop_gained | Exon 14 of 15 | NP_001121370.1 | P51795-2 | ||
| CLCN5 | c.2332C>T | p.Arg778* | stop_gained | Exon 14 of 15 | NP_001427685.1 | ||||
| CLCN5 | c.2332C>T | p.Arg778* | stop_gained | Exon 14 of 15 | NP_001427686.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CLCN5 | TSL:2 MANE Select | c.2320C>T | p.Arg774* | stop_gained | Exon 14 of 15 | ENSP00000365259.3 | P51795-2 | ||
| CLCN5 | TSL:1 | c.2110C>T | p.Arg704* | stop_gained | Exon 11 of 12 | ENSP00000304257.2 | P51795-1 | ||
| CLCN5 | TSL:1 | c.2110C>T | p.Arg704* | stop_gained | Exon 11 of 12 | ENSP00000365276.3 | P51795-1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
22
GnomAD4 exome AF: 0.00000273 AC: 3AN: 1097831Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1AN XY: 363215 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
3
AN:
1097831
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
363215
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
26390
American (AMR)
AF:
AC:
0
AN:
35195
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
19377
East Asian (EAS)
AF:
AC:
0
AN:
30202
South Asian (SAS)
AF:
AC:
0
AN:
54134
European-Finnish (FIN)
AF:
AC:
0
AN:
40528
Middle Eastern (MID)
AF:
AC:
0
AN:
4135
European-Non Finnish (NFE)
AF:
AC:
2
AN:
841787
Other (OTH)
AF:
AC:
1
AN:
46083
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.400
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
22
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
Pathogenic
VUS
Benign
Condition
1
1
-
X-linked recessive nephrolithiasis with renal failure (2)
1
-
-
CLCN5-related disorder (1)
1
-
-
Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;C1848336:Dent disease type 1 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
PhyloP100
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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