rs483352837
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_033056.4(PCDH15):c.2367_2369del(p.Val790del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000849 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000086 ( 0 hom. )
Consequence
PCDH15
NM_033056.4 inframe_deletion
NM_033056.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.08
Genes affected
PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_033056.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| PCDH15 | NM_001384140.1 | c.2367_2369del | p.Val790del | inframe_deletion | 19/38 | ENST00000644397.2 | |
| PCDH15 | NM_033056.4 | c.2367_2369del | p.Val790del | inframe_deletion | 19/33 | ENST00000320301.11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PCDH15 | ENST00000320301.11 | c.2367_2369del | p.Val790del | inframe_deletion | 19/33 | 1 | NM_033056.4 | ||
| PCDH15 | ENST00000644397.2 | c.2367_2369del | p.Val790del | inframe_deletion | 19/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000724 AC: 11AN: 152002Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
11
AN:
152002
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251246Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135776
GnomAD3 exomes
AF:
AC:
14
AN:
251246
Hom.:
AF XY:
AC XY:
11
AN XY:
135776
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000862 AC: 126AN: 1461770Hom.: 0 AF XY: 0.0000866 AC XY: 63AN XY: 727186
GnomAD4 exome
AF:
AC:
126
AN:
1461770
Hom.:
AF XY:
AC XY:
63
AN XY:
727186
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74366
GnomAD4 genome
?
AF:
AC:
11
AN:
152118
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
74366
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome type 1F Uncertain:3
| Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.Val790del variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 32835555, 25930172) and has been identified in 0.02% (3/19950) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs483352837). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 126521) and has been interpreted as pathogenic by Genomic Research Center (Shahid Beheshti University of Medical Sciences) and Institute of Otorhinolaryngology (Sun Yat-sen University) and as a variant of uncertain significance by Counsyl, Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine), Natera, Inc, and Women's Health and Genetics/Laboratory Corporation of America. Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Val790del variant is pathogenic (PMID: 25930172). This variant is a deletion of 1 amino acid at position 790 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, the clinical significance of the p.Val790del variant is uncertain. ACMG/AMP Criteria applied: PM4_supporting, PM3_supporting (Richards 2015). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 05, 2018 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 10, 2020 | - - |
Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:1Uncertain:1
| Pathogenic, flagged submission | literature only | Institute of Otorhinolaryngology, The First affiliated hospital, Sun Yat-sen University | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 30, 2023 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 10, 2020 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val790del variant in PCDH15 has been previously reported in the homozygous state in one individual with sensorineural hearing loss and segregated in an affected family member. The affected individuals were reported to be age 18 and 28 years, and did not report symptoms of night-blindness. However, electroretinograms were not obtained (Zhan 2015 PMID: 25930172). It has also been identified in one individual with hearing loss by our laboratory who was heterozygous for the variant. This variant has been reported in ClinVar (Variation ID 126521), and it also has been identified in several populations by gnomAD, with the highest frequency of 0.01% (3/19950) of East Asian European chromosomes (http://gnomad.broadinstitute.org). This variant is a deletion of a valine (Val) residue at position 790 and is not predicted to alter the protein reading-frame. It is unclear whether this deletion impacts the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Val790del variant is uncertain. ACMG/AMP criteria applied: PM3_Supporting, PM2_Supporting, PP1, PM4_Supporting. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2022 | Variant summary: PCDH15 c.2367_2369delTGT (p.Val790del) results in an in-frame deletion that is predicted to remove one amino acid from Cadherin-like domain (IPR002126, also known as EC7 domain (Zhan_2015)) the encoded protein. The variant allele was found at a frequency of 5.6e-05 in 251246 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (5.6e-05 vs 0.0032), allowing no conclusion about variant significance. c.2367_2369delTGT has been reported in the literature in one heterozygous individual affected with Usher Syndrome and one homozygous individual affected with non-syndromic hearing loss (Zhan_2015, Zheng_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | This variant, c.2367_2369del, results in the deletion of 1 amino acid(s) of the PCDH15 protein (p.Val790del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs483352837, gnomAD 0.02%). This variant has been observed in individual(s) with PCDH15-related conditions (PMID: 25930172, 32835555). ClinVar contains an entry for this variant (Variation ID: 126521). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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