rs79854148

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033056.4(PCDH15):c.5707A>G(p.Ile1903Val) variant causes a missense change. The variant allele was found at a frequency of 0.00666 in 1,614,002 control chromosomes in the GnomAD database, including 643 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. I1903T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 327 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 316 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.88

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 23
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

PCDH15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016710162).

BP6

Variant 10-53822019-T-C is Benign according to our data. Variant chr10-53822019-T-C is described in ClinVar as [Benign]. Clinvar id is 46507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.5707A>G	p.Ile1903Val	missense_variant	Exon 33 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.4368-1789A>G		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.5707A>G	p.Ile1903Val	missense_variant	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.4368-1789A>G		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.0352

AC:

5356

AN:

152148

Hom.:

328

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.00954

AC:

2398

AN:

251328

AF XY:

0.00720

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.00662

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00368

AC:

5375

AN:

1461736

Hom.:

316

Cov.:

AF XY:

0.00322

AC XY:

2343

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.127

AC:

4258

AN:

33470

American (AMR)

AF:

0.00725

AC:

324

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000441

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000151

AC:

168

AN:

1111892

Other (OTH)

AF:

0.00891

AC:

538

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

321

642

963

1284

1605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0353

AC:

5371

AN:

152266

Hom.:

327

Cov.:

AF XY:

0.0342

AC XY:

2547

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.123

AC:

5099

AN:

41542

American (AMR)

AF:

0.0130

AC:

199

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68024

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

240

480

721

961

1201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0138

Hom.:

240

Bravo

AF:

0.0398

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.122

AC:

539

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.0120

AC:

1452

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 01, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ile1903Val in exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because has been identified with a frequency of 21% in the West Afri can population (dbSNP rs79854148). In addition, this residue is not conserved in mammals and this variant occurs at an equal frequency in probands (1/113) and c ontrols (1/80) (Ouyang 2005). -

Oct 05, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 20, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Aug 31, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

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

- -

Usher syndrome type 1F

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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

0.12

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0095

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

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

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

MetaRNN

Benign

0.0017

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

.;.;.;.;.;.;.;.;M

PhyloP100

3.9

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.11

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

REVEL

Benign

0.13

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.080

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

Polyphen

0.82

P;.;.;P;P;P;.;P;P

Vest4

0.18

MPC

0.025

ClinPred

0.049

GERP RS

5.3

Varity_R

0.18

gMVP

0.17

Mutation Taster

=70/30

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over