rs141169746
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_033056.4(PCDH15):c.1028G>A(p.Arg343Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000582 in 1,611,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_033056.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.1028G>A | p.Arg343Lys | missense_variant | 10/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.1028G>A | p.Arg343Lys | missense_variant | 10/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.1028G>A | p.Arg343Lys | missense_variant | 10/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.1028G>A | p.Arg343Lys | missense_variant | 10/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.000519 AC: 79AN: 152094Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000167 AC: 42AN: 251294Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135814
GnomAD4 exome AF: 0.000589 AC: 859AN: 1459486Hom.: 0 Cov.: 30 AF XY: 0.000594 AC XY: 431AN XY: 726196
GnomAD4 genome ? AF: 0.000519 AC: 79AN: 152094Hom.: 0 Cov.: 33 AF XY: 0.000539 AC XY: 40AN XY: 74280
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 343 of the PCDH15 protein (p.Arg343Lys). This variant is present in population databases (rs141169746, gnomAD 0.04%). 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: 46433). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 30, 2022 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 15, 2017 | p.Arg343Lys in exon 10 of PCDH155: This variant is not expected to have clinical significance because the Arg residue at position 343 is not well conserved acro ss distant species, computational analysis do not suggest a high likelihood of i mpact to the protein, and it has been identified in 50/126580 European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141169746). Furthermore, it has been identified in cis with a pathogeni c variant in PCDH15 in an individual with Usher syndrome. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at