ENST00000395445.6:c.4832A>C

Variant names:

Variant summary

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

The ENST00000395445.6(PCDH15):c.4832A>C(p.Glu1611Ala) variant causes a missense change. The variant allele was found at a frequency of 0.196 in 1,613,746 control chromosomes in the GnomAD database, including 40,912 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1611D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.19 ( 3674 hom., cov: 32)

Exomes 𝑓: 0.20 ( 37238 hom. )

Consequence

PCDH15
ENST00000395445.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.64

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.748185E-6).

BP6

Variant 10-53809212-T-G is Benign according to our data. Variant chr10-53809212-T-G is described in ClinVar as [Benign]. Clinvar id is 44035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809212-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001384140.1 link	c.4671+1344A>C		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+1344A>C		intron_variant	Intron 37 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28359

AN:

152004

Hom.:

3676

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.214

Gnomad AMR

AF:

0.264

Gnomad ASJ

AF:

0.195

Gnomad EAS

AF:

0.697

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.170

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.187

GnomAD3 exomes

AF:

0.254

AC:

63144

AN:

248664

Hom.:

11179

AF XY:

0.249

AC XY:

33669

AN XY:

135116

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.392

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.703

Gnomad SAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.197

AC:

288518

AN:

1461626

Hom.:

37238

Cov.:

AF XY:

0.200

AC XY:

145478

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.115

Gnomad4 AMR exome

AF:

0.374

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.741

Gnomad4 SAS exome

AF:

0.320

Gnomad4 FIN exome

AF:

0.173

Gnomad4 NFE exome

AF:

0.165

Gnomad4 OTH exome

AF:

0.206

GnomAD4 genome

AF:

0.186

AC:

28368

AN:

152120

Hom.:

3674

Cov.:

AF XY:

0.194

AC XY:

14444

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.117

Gnomad4 AMR

AF:

0.265

Gnomad4 ASJ

AF:

0.195

Gnomad4 EAS

AF:

0.697

Gnomad4 SAS

AF:

0.328

Gnomad4 FIN

AF:

0.170

Gnomad4 NFE

AF:

0.165

Gnomad4 OTH

AF:

0.189

Alfa

AF:

0.181

Hom.:

5571

Bravo

AF:

0.194

TwinsUK

AF:

0.161

AC:

598

ALSPAC

AF:

0.172

AC:

664

ESP6500AA

AF:

0.121

AC:

381

ESP6500EA

AF:

0.161

AC:

1150

ExAC

AF:

0.249

AC:

29937

Asia WGS

AF:

0.441

AC:

1532

AN:

3478

EpiCase

AF:

0.161

EpiControl

AF:

0.161

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Glu1618Ala in Exon 36 of PCDH15: This variant is not expected to have clinical s ignificance because it has been identified in 16.2% (884/5446) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs11003863). -

Feb 21, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 23

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

.;.;.;T;.;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.77

T;T;T;T;T;T

MetaRNN

Benign

0.0000037

T;T;T;T;T;T

MetaSVM

Benign

-0.92

PROVEAN

Benign

-0.11

N;N;N;.;N;.

REVEL

Benign

0.051

Sift

Uncertain

0.0030

D;D;D;.;D;.

Sift4G

Uncertain

0.038

D;T;T;T;T;T

Vest4

0.31

ClinPred

0.029

GERP RS

4.6

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