rs138744579
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001384140.1(PCDH15):c.875C>T(p.Pro292Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,612,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
PCDH15
NM_001384140.1 missense, splice_region
NM_001384140.1 missense, splice_region
Scores
3
9
7
Splicing: ADA: 0.9711
2
Clinical Significance
Conservation
PhyloP100: 9.77
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.875C>T | p.Pro292Leu | missense_variant, splice_region_variant | 8/33 | ENST00000320301.11 | NP_149045.3 | |
PCDH15 | NM_001384140.1 | c.875C>T | p.Pro292Leu | missense_variant, splice_region_variant | 8/38 | ENST00000644397.2 | NP_001371069.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.875C>T | p.Pro292Leu | missense_variant, splice_region_variant | 8/33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
PCDH15 | ENST00000644397.2 | c.875C>T | p.Pro292Leu | missense_variant, splice_region_variant | 8/38 | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes AF: 0.000132 AC: 20AN: 152028Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251218Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135766
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GnomAD4 exome AF: 0.0000384 AC: 56AN: 1460086Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 726486
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GnomAD4 genome AF: 0.000138 AC: 21AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 17, 2023 | The c.875C>T (p.P292L) alteration is located in exon 8 (coding exon 7) of the PCDH15 gene. This alteration results from a C to T substitution at nucleotide position 875, causing the proline (P) at amino acid position 292 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 292 of the PCDH15 protein (p.Pro292Leu). This variant is present in population databases (rs138744579, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;.;M;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL
Uncertain
Sift
Benign
T;.;.;T;.;.;D;D;.;T;.;T;T;.;T;.;.;D;D;D;.;D;D;D
Sift4G
Uncertain
D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0, 1.0, 0.98
.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4
MVP
MPC
0.22
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at