rs745335831
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_033056.4(PCDH15):c.4925G>A(p.Gly1642Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
PCDH15
NM_033056.4 missense
NM_033056.4 missense
Scores
17
Clinical Significance
Conservation
PhyloP100: 4.01
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 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.08502504).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.4925G>A | p.Gly1642Asp | missense_variant | 33/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.4368-2571G>A | intron_variant | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.4925G>A | p.Gly1642Asp | missense_variant | 33/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.4368-2571G>A | intron_variant | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152146Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
7
AN:
152146
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: 0.00000398 AC: 1AN: 251396Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135854
GnomAD3 exomes
AF:
AC:
1
AN:
251396
Hom.:
AF XY:
AC XY:
0
AN XY:
135854
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: 6.84e-7 AC: 1AN: 1461758Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727156
GnomAD4 exome
AF:
AC:
1
AN:
1461758
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
727156
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: 0.0000460 AC: 7AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74326
GnomAD4 genome
?
AF:
AC:
7
AN:
152146
Hom.:
Cov.:
32
AF XY:
AC XY:
7
AN XY:
74326
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:
ExAC
?
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 10, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 22, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Gly1642Asp va riant in PCDH15 has not been previously reported in individuals with hearing los s or Usher syndrome. This variant has been identified in 1/10406 African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs745335831); however, this frequency is not high enough to rule out a pat hogenic role. The glycine (Gly) at position 1642 is not conserved in mammals or evolutionarily distant species, supporting that a change at this position may be tolerated. Additional computational prediction tools suggest that the p.Gly1642 Asp variant may not impact the protein, though this information is not predictiv e enough to rule out pathogenicity. In summary, while the clinical significance of the p.Gly1642Asp variant is uncertain, these data suggest that it is more lik ely to be benign. - |
Usher syndrome type 1F Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 27, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces glycine with aspartic acid at codon 1642 of the PCDH15 protein (p.Gly1642Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs745335831, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 505300). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;N;N;.;N;N
REVEL
Benign
Sift
Benign
T;.;.;T;T;T;.;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
B;.;.;B;P;B;.;B;B
Vest4
MVP
MPC
0.032
ClinPred
T
GERP RS
Varity_R
gMVP
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