rs397517932
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_174878.3(CLRN1):c.301_305delGTCAT(p.Val101SerfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CLRN1
NM_174878.3 frameshift
NM_174878.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.81
Publications
5 publications found
Genes affected
CLRN1 (HGNC:12605): (clarin 1) This gene encodes a protein that contains a cytosolic N-terminus, multiple helical transmembrane domains, and an endoplasmic reticulum membrane retention signal, TKGH, in the C-terminus. The encoded protein may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIIa. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
ENSG00000260234 (HGNC:):
Genome browser will be placed here
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 3-150941709-AATGAC-A is Pathogenic according to our data. Variant chr3-150941709-AATGAC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 48145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_174878.3. 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 |
|---|---|---|---|---|---|---|---|---|---|
| CLRN1 | MANE Select | c.301_305delGTCAT | p.Val101SerfsTer27 | frameshift | Exon 2 of 3 | NP_777367.1 | P58418-3 | ||
| CLRN1 | c.301_305delGTCAT | p.Val101SerfsTer27 | frameshift | Exon 2 of 4 | NP_001182723.1 | P58418-4 | |||
| CLRN1 | c.473_477delGTCAT | p.Cys158PhefsTer10 | frameshift | Exon 3 of 4 | NP_001243748.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CLRN1 | TSL:1 MANE Select | c.301_305delGTCAT | p.Val101SerfsTer27 | frameshift | Exon 2 of 3 | ENSP00000322280.1 | P58418-3 | ||
| CLRN1 | TSL:1 | c.301_305delGTCAT | p.Val101SerfsTer27 | frameshift | Exon 2 of 4 | ENSP00000329158.4 | P58418-4 | ||
| CLRN1 | TSL:1 | c.73_77delGTCAT | p.Val25SerfsTer27 | frameshift | Exon 2 of 4 | ENSP00000295911.2 | P58418-1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000796 AC: 2AN: 251374 AF XY: 0.00000736 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
251374
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
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Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461766Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727176 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1461766
Hom.:
AF XY:
AC XY:
2
AN XY:
727176
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33478
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26132
East Asian (EAS)
AF:
AC:
0
AN:
39682
South Asian (SAS)
AF:
AC:
0
AN:
86250
European-Finnish (FIN)
AF:
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
2
AN:
1111924
Other (OTH)
AF:
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
not provided (2)
1
-
-
Rare genetic deafness (1)
1
-
-
Retinitis pigmentosa 61;C5779850:Usher syndrome type 3A (1)
1
-
-
Usher syndrome (1)
1
-
-
Usher syndrome type 3 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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