chr10-53903293-C-T
Variant names:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2
The NM_001384140.1(PCDH15):c.3451G>A(p.Gly1151Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00035 in 1,613,102 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 2 hom. )
Consequence
PCDH15
NM_001384140.1 missense
NM_001384140.1 missense
Scores
9
5
4
Clinical Significance
Conservation
PhyloP100: 7.07
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 Benign. Variant got -19 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.009842426).
BP6
Variant 10-53903293-C-T is Benign according to our data. Variant chr10-53903293-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 179960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53903293-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000526 (80/152184) while in subpopulation EAS AF= 0.0143 (74/5174). AF 95% confidence interval is 0.0117. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.3451G>A | p.Gly1151Arg | missense_variant | Exon 26 of 33 | 1 | NM_033056.4 | ENSP00000322604.6 | ||
PCDH15 | ENST00000644397.2 | c.3451G>A | p.Gly1151Arg | missense_variant | Exon 26 of 38 | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes AF: 0.000526 AC: 80AN: 152066Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00131 AC: 329AN: 250984Hom.: 2 AF XY: 0.00128 AC XY: 174AN XY: 135684
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GnomAD4 exome AF: 0.000331 AC: 484AN: 1460918Hom.: 2 Cov.: 31 AF XY: 0.000319 AC XY: 232AN XY: 726790
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GnomAD4 genome AF: 0.000526 AC: 80AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.000726 AC XY: 54AN XY: 74402
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 02, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 18, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 12, 2022 | Variant summary: PCDH15 c.3451G>A (p.Gly1151Arg) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 250984 control chromosomes, predominantly at a frequency of 0.017 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=3) and benign (n=3). Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 12, 2017 | p.Gly1151Arg in exon 26 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 1.7% (322/18942) of East Asian c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org/; dbSNP rs149478475). - |
Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 20, 2021 | - - |
Usher syndrome type 1F Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 16, 2020 | - - |
Usher syndrome type 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
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
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;.;.;.;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D
REVEL
Uncertain
Sift
Uncertain
.;.;.;.;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D
Sift4G
Pathogenic
D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0047);Gain of MoRF binding (P = 0.0047);.;Gain of MoRF binding (P = 0.0047);Gain of MoRF binding (P = 0.0047);.;Gain of MoRF binding (P = 0.0047);.;.;.;Gain of MoRF binding (P = 0.0047);.;.;.;.;Gain of MoRF binding (P = 0.0047);Gain of MoRF binding (P = 0.0047);.;.;.;Gain of MoRF binding (P = 0.0047);
MVP
MPC
0.24
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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