rs11004439

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001384140.1(PCDH15):c.55T>G(p.Ser19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,610,862 control chromosomes in the GnomAD database, including 44,316 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S19T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.20 ( 3422 hom., cov: 31)

Exomes 𝑓: 0.23 ( 40894 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.188

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012873054).

BP6

Variant 10-54664208-A-C is Benign according to our data. Variant chr10-54664208-A-C is described in ClinVar as [Benign]. Clinvar id is 46504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54664208-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.55T>G	p.Ser19Ala	missense_variant	2/33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 linkuse as main transcript	c.55T>G	p.Ser19Ala	missense_variant	2/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.55T>G	p.Ser19Ala	missense_variant	2/33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.55T>G	p.Ser19Ala	missense_variant	2/38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.204

AC:

31001

AN:

151808

Hom.:

3424

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.322

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.245

Gnomad OTH

AF:

0.243

GnomAD3 exomes

AF:

0.221

AC:

55151

AN:

250098

Hom.:

6698

AF XY:

0.218

AC XY:

29415

AN XY:

135170

show subpopulations

Gnomad AFR exome

AF:

0.141

Gnomad AMR exome

AF:

0.293

Gnomad ASJ exome

AF:

0.317

Gnomad EAS exome

AF:

0.139

Gnomad SAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.247

Gnomad OTH exome

AF:

0.236

GnomAD4 exome

AF:

0.232

AC:

338249

AN:

1458936

Hom.:

40894

Cov.:

AF XY:

0.230

AC XY:

167052

AN XY:

725862

show subpopulations

Gnomad4 AFR exome

AF:

0.141

Gnomad4 AMR exome

AF:

0.287

Gnomad4 ASJ exome

AF:

0.314

Gnomad4 EAS exome

AF:

0.118

Gnomad4 SAS exome

AF:

0.149

Gnomad4 FIN exome

AF:

0.149

Gnomad4 NFE exome

AF:

0.245

Gnomad4 OTH exome

AF:

0.229

GnomAD4 genome

AF:

0.204

AC:

31010

AN:

151926

Hom.:

3422

Cov.:

AF XY:

0.199

AC XY:

14783

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.140

Gnomad4 AMR

AF:

0.245

Gnomad4 ASJ

AF:

0.322

Gnomad4 EAS

AF:

0.127

Gnomad4 SAS

AF:

0.144

Gnomad4 FIN

AF:

0.147

Gnomad4 NFE

AF:

0.245

Gnomad4 OTH

AF:

0.241

Alfa

AF:

0.243

Hom.:

11500

Bravo

AF:

0.217

TwinsUK

AF:

0.244

AC:

904

ALSPAC

AF:

0.232

AC:

893

ESP6500AA

AF:

0.150

AC:

662

ESP6500EA

AF:

0.250

AC:

2148

ExAC

AF:

0.214

AC:

26012

Asia WGS

AF:

0.125

AC:

437

AN:

3478

EpiCase

AF:

0.257

EpiControl

AF:

0.262

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2016	Variant summary: The PCDH15 c.55T>G variant affects a non-conserved nucleotide, resulting in amino acid change from Ser to Ala. 3/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 25808/118352 control chromosomes (3055 homozygotes) at a frequency of 0.2180614, which is about 69 times of the maximal expected frequency of a pathogenic PCDH15 allele (0.0031623), suggesting this variant is a benign polymorphism. This variant is reported in USH patients without evidence for causality and authors listed the variant as a frequent SNP. In addition, one reputable clinical laboratory via ClinVar classified this variant as benign. Taken together, this variant was classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 1F

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Autosomal recessive nonsyndromic hearing loss 23

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Usher syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.4

DANN

Benign

0.92

DEOGEN2

Benign

0.012

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.45

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

MetaRNN

Benign

0.013

T;T;T;T;T;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

0.69

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

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.72

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

REVEL

Benign

0.019

Sift

Benign

0.11

T;.;.;T;.;.;T;T;.;T;.;T;T;.;D;.;.;D;D;D;D;D;D;T;.;T

Sift4G

Benign

0.13

T;.;T;T;T;T;T;D;T;D;T;D;T;T;D;T;D;D;D;D;T;D;D;T;.;.

Polyphen

0.0, 0.059, 0.033, 0.11, 0.023

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

Vest4

0.061

MPC

0.025

ClinPred

0.0012

GERP RS

0.64

Varity_R

0.062

gMVP

0.24

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