rs61731363
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_033056.4(PCDH15):c.2435T>C(p.Ile812Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,613,974 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I812M) has been classified as Uncertain significance.
Frequency
Consequence
NM_033056.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.2435T>C | p.Ile812Thr | missense_variant | 19/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.2435T>C | p.Ile812Thr | missense_variant | 19/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.2435T>C | p.Ile812Thr | missense_variant | 19/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.2435T>C | p.Ile812Thr | missense_variant | 19/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.00309 AC: 470AN: 152112Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000696 AC: 175AN: 251336Hom.: 0 AF XY: 0.000545 AC XY: 74AN XY: 135840
GnomAD4 exome AF: 0.000335 AC: 490AN: 1461744Hom.: 2 Cov.: 31 AF XY: 0.000278 AC XY: 202AN XY: 727166
GnomAD4 genome ? AF: 0.00315 AC: 479AN: 152230Hom.: 2 Cov.: 32 AF XY: 0.00288 AC XY: 214AN XY: 74428
ClinVar
Submissions by phenotype
not provided Benign:6
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Apr 11, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 14, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 17, 2021 | This variant is associated with the following publications: (PMID: 27766948) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 12, 2022 | Variant summary: PCDH15 c.2435T>C (p.Ile812Thr) 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 0.0031 in 152112 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD v3 database (genomes data), including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.5 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 African or African-American 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=4) and benign (n=2). 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 | May 07, 2012 | Ile812Thr in Exon 19 of PCDH15: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (26/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs61731363). - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 19, 2014 | - - |
Usher syndrome type 1F Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Jan 09, 2017 | - - |
Usher syndrome type 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at