rs483353074

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_001142769.3(PCDH15):c.4673_4676delTTAG(p.Val1558GlufsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

PCDH15
NM_001142769.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.37

Variant links:

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]

PCDH15 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.13 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-53809388-TCTAA-T is Pathogenic according to our data. Variant chr10-53809388-TCTAA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44034.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001384140.1 link	c.4671+1164_4671+1167delTTAG		intron_variant	Intron 37 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2 link	c.4671+1164_4671+1167delTTAG		intron_variant	Intron 37 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000523

AC:

AN:

248800

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000623

AC:

AN:

1461692

Hom.:

AF XY:

0.0000564

AC XY:

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000782

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000642

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 23

Pathogenic:1

Feb 28, 2023

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant occurred in compound heterozygosity with a PCHD15 missense variant in an individual with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). At the time of recruitment, this patient did not have any known visual impairment (age 13y). This patient's family has no other history of hearing loss. This variant is a 4bp deletion that causes a frameshift which is predicted to lead to the addition of 3 incorrect amino acids and introduce an early stop at position 1560 of the otherwise 1783 amino acid length protein. Only the PDCH15 isoform critical to hearing, and not the others, would be changed by this variant (PMID: 32747562, 24940003). As of January 2023, this variant has been reported previously in an individual with hearing loss and is currently classified as a variant of unknown significance to ClinVar, and it is found in 13 heterozygous individuals on gnomAD. Based on the prediction that this variant leads to a truncated protein and goodness of fit of genotype to phenotype, we conclude that this variant is pathogenic. -

not specified

Uncertain:1

Sep 22, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val1558fs variant in PCDH15 has been reported in two individuals with hear ing loss; however, a variant affecting the remaining copy of PCDH15 was not iden tified in any of these individuals (Sloan-Heggen 2016, LMM data). This variant h as been identified in 8/66278 European chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs483353074); however, its f requency is not high enough to rule out a pathogenic role. This variant affects the coding region of only one minor transcript of the PCDH15 gene, and is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 1558 and leads to a premature termination codon 3 amino acids do wnstream in a minor isoform of the protein. This termination codon occurs within the terminal 50 bases of the last exon, likely to escape nonsense mediated deca y (NMD) and result in a truncated protein. The functional impact of this truncat ion is unclear. In summary, the clinical significance of the p.Val1558fs variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over