rs1168400018
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_033056.4(PCDH15):c.145G>T(p.Glu49Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,458,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
PCDH15
NM_033056.4 stop_gained
NM_033056.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 4.80
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 10-54527824-C-A is Pathogenic according to our data. Variant chr10-54527824-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.145G>T | p.Glu49Ter | stop_gained | 3/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.145G>T | p.Glu49Ter | stop_gained | 3/38 | ENST00000644397.2 | |
LOC105378311 | NR_134503.1 | n.88-40741C>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.145G>T | p.Glu49Ter | stop_gained | 3/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.145G>T | p.Glu49Ter | stop_gained | 3/38 | NM_001384140.1 | |||
ENST00000422842.1 | n.88-40741C>A | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1458230Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2AN XY: 725440
GnomAD4 exome
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6
AN:
1458230
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30
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2
AN XY:
725440
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 27, 2023 | - - |
Usher syndrome type 1F Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 09, 2023 | This sequence change creates a premature translational stop signal (p.Glu49*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with PCDH15-related conditions (PMID: 26166082). ClinVar contains an entry for this variant (Variation ID: 554937). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A;A;D;D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at