rs797044813
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001440756.1(CLCN5):c.2131C>T(p.Arg711*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,652 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )
Consequence
CLCN5
NM_001440756.1 stop_gained
NM_001440756.1 stop_gained
Scores
2
2
Clinical Significance
Conservation
PhyloP100: 1.22
Publications
13 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 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-50090490-C-T is Pathogenic according to our data. Variant chrX-50090490-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 207999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001440756.1. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CLCN5 | NM_001127898.4 | MANE Select | c.2119C>T | p.Arg707* | stop_gained | Exon 13 of 15 | NP_001121370.1 | ||
| CLCN5 | NM_001440756.1 | c.2131C>T | p.Arg711* | stop_gained | Exon 13 of 15 | NP_001427685.1 | |||
| CLCN5 | NM_001440757.1 | c.2131C>T | p.Arg711* | stop_gained | Exon 13 of 15 | NP_001427686.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CLCN5 | ENST00000376091.8 | TSL:2 MANE Select | c.2119C>T | p.Arg707* | stop_gained | Exon 13 of 15 | ENSP00000365259.3 | ||
| CLCN5 | ENST00000307367.2 | TSL:1 | c.1909C>T | p.Arg637* | stop_gained | Exon 10 of 12 | ENSP00000304257.2 | ||
| CLCN5 | ENST00000376108.7 | TSL:1 | c.1909C>T | p.Arg637* | stop_gained | Exon 10 of 12 | ENSP00000365276.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
22
GnomAD4 exome AF: 9.14e-7 AC: 1AN: 1094652Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 360346 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1094652
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
360346
show subpopulations
African (AFR)
AF:
AC:
0
AN:
26352
American (AMR)
AF:
AC:
0
AN:
34862
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
19329
East Asian (EAS)
AF:
AC:
0
AN:
30118
South Asian (SAS)
AF:
AC:
0
AN:
53495
European-Finnish (FIN)
AF:
AC:
0
AN:
40307
Middle Eastern (MID)
AF:
AC:
0
AN:
4129
European-Non Finnish (NFE)
AF:
AC:
1
AN:
840073
Other (OTH)
AF:
AC:
0
AN:
45987
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
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 as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
4
-
-
not provided (4)
1
-
-
Dent disease (1)
1
-
-
Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis (1)
1
-
-
X-linked recessive nephrolithiasis with renal failure;C1839874:Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;C1845168:Hypophosphatemic rickets, X-linked recessive;C1848336:Dent disease type 1 (1)
-
-
-
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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