chr10-54183578-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001384140.1(PCDH15):c.1456G>A(p.Gly486Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
PCDH15
NM_001384140.1 missense
NM_001384140.1 missense
Scores
4
9
6
Clinical Significance
Conservation
PhyloP100: 7.81
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.1456G>A | p.Gly486Ser | missense_variant | Exon 13 of 33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
PCDH15 | ENST00000644397.2 | c.1456G>A | p.Gly486Ser | missense_variant | Exon 13 of 38 | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251298Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135812
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461652Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727140
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome type 1F Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.Gly486Ser variant in PCDH15 has been reported in 1 individual with Usher syndrome type 1F (PMID: 27610647) and has been identified in 0.007% (2/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1196401374). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 558525) and has been interpreted as a variant of uncertain significance by Counsyl. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly486Ser variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting (Richards 2015). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 24, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2024 | Variant summary: PCDH15 c.1456G>A (p.Gly486Ser) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251298 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1456G>A has been reported in the literature as a non-informative genotype (second allele and/or zygosity not specified) in a cohort of individuals with hearing loss (example, Chen_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27610647). ClinVar contains an entry for this variant (Variation ID: 558525). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;T;T;.;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
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
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;.;.;.;.;.;D;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D
REVEL
Uncertain
Sift
Benign
.;.;.;.;.;.;.;T;D;.;D;D;.;T;.;.;T;T;T;.;T;T;D
Sift4G
Pathogenic
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, 0.98
.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D
Vest4
MutPred
Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);.;Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);.;Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);.;.;.;Gain of disorder (P = 0.0621);.;.;.;Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);.;.;Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);Gain of disorder (P = 0.0621);
MVP
MPC
0.21
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at