rs45483395

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BS1BS2

The NM_001384140.1(PCDH15):c.2885G>T(p.Arg962Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,608,790 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R962C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 9 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 1.20

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 -11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-53961877-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.009616345).

BP6

Variant 10-53961876-C-A is Benign according to our data. Variant chr10-53961876-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46458.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=2}. Variant chr10-53961876-C-A is described in Lovd as [Benign]. Variant chr10-53961876-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00304 (462/152180) while in subpopulation AMR AF= 0.00851 (130/15278). AF 95% confidence interval is 0.00732. There are 2 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.2885G>T	p.Arg962Leu	missense_variant	Exon 22 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.2885G>T	p.Arg962Leu	missense_variant	Exon 22 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.2885G>T	p.Arg962Leu	missense_variant	Exon 22 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.2885G>T	p.Arg962Leu	missense_variant	Exon 22 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.00304

AC:

462

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00859

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00354

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00267

AC:

671

AN:

250940

Hom.:

AF XY:

0.00273

AC XY:

370

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00498

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00189

Gnomad NFE exome

AF:

0.00360

Gnomad OTH exome

AF:

0.00475

GnomAD4 exome

AF:

0.00300

AC:

4377

AN:

1456610

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

2165

AN XY:

724762

show subpopulations

Gnomad4 AFR exome

AF:

0.000840

Gnomad4 AMR exome

AF:

0.00501

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.00193

Gnomad4 NFE exome

AF:

0.00347

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.00304

AC:

462

AN:

152180

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

227

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00340

Gnomad4 NFE

AF:

0.00354

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00376

Hom.:

Bravo

AF:

0.00304

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00311

AC:

ExAC

AF:

0.00208

AC:

253

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 26, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCDH15: BP4, BS1, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg962Leu in exon 22 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.3% (35/11558) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45483395). In addition, a different variant at the same position (p.Arg 962His) has also been identified in 0.7% (73/10320) of African chromosomes (ExAC , http://exac.broadinstitute.org; dbSNP rs45483395). The arginine (Arg) at posit ion 962 is not conserved in mammals or evolutionarily distant species and 5 spec ies (Zebra finch, and 4 fish) carry a leucine (Leu) at this position, raising th e possibility that this change may be tolerated. Additional computational predic tion tools suggest that this variant may not impact the protein. -

Usher syndrome type 1F

Benign:2

Nov 11, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

PCDH15-related disorder

Benign:1

Jul 02, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.019

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

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.027

MetaRNN

Benign

0.0096

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.58

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

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.13

Sift

Benign

0.16

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

Sift4G

Benign

0.23

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

Polyphen

0.0010, 0.013, 0.023, 0.97, 0.10, 0.039

.;.;.;.;.;.;.;.;.;.;B;.;B;.;.;B;D;D;.;B;B

Vest4

0.32

MVP

0.62

MPC

0.032

ClinPred

0.022

GERP RS

1.7

Varity_R

0.25

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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