rs114137983

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_033056.4(PCDH15):c.5414C>T(p.Pro1805Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,609,358 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.56

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047721267).

BP6

Variant 10-53822312-G-A is Benign according to our data. Variant chr10-53822312-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46500.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=1}. Variant chr10-53822312-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00208 (316/152020) while in subpopulation AFR AF= 0.006 (249/41494). AF 95% confidence interval is 0.00539. There are 0 homozygotes in gnomad4. There are 144 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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.5414C>T	p.Pro1805Leu	missense_variant	Exon 33 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.4368-2082C>T		intron_variant	Intron 32 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.5414C>T	p.Pro1805Leu	missense_variant	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.4368-2082C>T		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

317

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000775

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00385

GnomAD3 exomes

AF:

0.00107

AC:

255

AN:

238988

Hom.:

AF XY:

0.000921

AC XY:

119

AN XY:

129178

show subpopulations

Gnomad AFR exome

AF:

0.00700

Gnomad AMR exome

AF:

0.00199

Gnomad ASJ exome

AF:

0.000709

Gnomad EAS exome

AF:

0.000684

Gnomad SAS exome

AF:

0.0000999

Gnomad FIN exome

AF:

0.000141

Gnomad NFE exome

AF:

0.000455

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.000581

AC:

847

AN:

1457338

Hom.:

Cov.:

AF XY:

0.000542

AC XY:

393

AN XY:

724566

show subpopulations

Gnomad4 AFR exome

AF:

0.00741

Gnomad4 AMR exome

AF:

0.00222

Gnomad4 ASJ exome

AF:

0.000460

Gnomad4 EAS exome

AF:

0.00126

Gnomad4 SAS exome

AF:

0.0000698

Gnomad4 FIN exome

AF:

0.000132

Gnomad4 NFE exome

AF:

0.000292

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.00208

AC:

316

AN:

152020

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

144

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00600

Gnomad4 AMR

AF:

0.00184

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000777

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00381

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00257

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00636

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000957

AC:

116

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCDH15: BP4 -

Jul 16, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro1805Leu in Exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (23/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs114137983). -

Jul 10, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

PCDH15-related disorder

Benign:1

Dec 21, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Usher syndrome type 1F

Benign:1

Dec 12, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

6.0

DANN

Benign

0.93

DEOGEN2

Benign

0.019

.;T;.;.;.;.;.;.;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.53

LIST_S2

Uncertain

0.86

D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.068

MetaRNN

Benign

0.0048

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.6

.;.;.;.;.;.;.;.;L

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.52

N;.;.;N;N;N;.;N;N

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;.;.;D;D;D;.;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D

Polyphen

0.45

B;.;.;B;B;B;.;B;B

Vest4

0.10

MVP

0.74

MPC

0.028

ClinPred

0.053

GERP RS

3.5

Varity_R

0.066

gMVP

0.20

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