10-53995731-C-T

Variant names:

Variant summary

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

The NM_001384140.1(PCDH15):c.2786G>A(p.Arg929Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,613,478 control chromosomes in the GnomAD database, including 44,202 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 (★★).

Frequency

Genomes: 𝑓 0.23 ( 4506 hom., cov: 32)

Exomes 𝑓: 0.22 ( 39696 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.850

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=9.7762146E-5).

BP6

Variant 10-53995731-C-T is Benign according to our data. Variant chr10-53995731-C-T is described in ClinVar as [Benign]. Clinvar id is 46456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53995731-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.2786G>A	p.Arg929Gln	missense_variant	Exon 21 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.2786G>A	p.Arg929Gln	missense_variant	Exon 21 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.2786G>A	p.Arg929Gln	missense_variant	Exon 21 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.2786G>A	p.Arg929Gln	missense_variant	Exon 21 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35400

AN:

151858

Hom.:

4509

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.303

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.505

Gnomad SAS

AF:

0.420

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.202

Gnomad OTH

AF:

0.214

GnomAD3 exomes

AF:

0.252

AC:

63196

AN:

250772

Hom.:

9077

AF XY:

0.259

AC XY:

35100

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.245

Gnomad AMR exome

AF:

0.202

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.476

Gnomad SAS exome

AF:

0.412

Gnomad FIN exome

AF:

0.239

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.221

AC:

322360

AN:

1461502

Hom.:

39696

Cov.:

AF XY:

0.226

AC XY:

164513

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.242

Gnomad4 AMR exome

AF:

0.203

Gnomad4 ASJ exome

AF:

0.177

Gnomad4 EAS exome

AF:

0.511

Gnomad4 SAS exome

AF:

0.411

Gnomad4 FIN exome

AF:

0.235

Gnomad4 NFE exome

AF:

0.196

Gnomad4 OTH exome

AF:

0.228

GnomAD4 genome

AF:

0.233

AC:

35422

AN:

151976

Hom.:

4506

Cov.:

AF XY:

0.239

AC XY:

17760

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.241

Gnomad4 AMR

AF:

0.210

Gnomad4 ASJ

AF:

0.184

Gnomad4 EAS

AF:

0.505

Gnomad4 SAS

AF:

0.420

Gnomad4 FIN

AF:

0.233

Gnomad4 NFE

AF:

0.202

Gnomad4 OTH

AF:

0.215

Alfa

AF:

0.206

Hom.:

8510

Bravo

AF:

0.226

TwinsUK

AF:

0.187

AC:

695

ALSPAC

AF:

0.201

AC:

775

ESP6500AA

AF:

0.233

AC:

1027

ESP6500EA

AF:

0.200

AC:

1719

ExAC

AF:

0.256

AC:

31094

Asia WGS

AF:

0.424

AC:

1475

AN:

3478

EpiCase

AF:

0.190

EpiControl

AF:

0.187

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 23, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F

Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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

0.11

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.0042

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

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.094

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;D;D;D;D;D;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.000098

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

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.57

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

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.21

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

REVEL

Benign

0.016

Sift

Benign

0.38

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

Sift4G

Benign

0.15

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

Polyphen

0.010, 0.067, 0.11, 0.29, 0.014

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

Vest4

0.10

MPC

0.032

ClinPred

0.00056

GERP RS

3.0

Varity_R

0.066

gMVP

0.30

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