rs11004439

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.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. 15/21 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 Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S19T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.20 ( 3422 hom., cov: 31)

Exomes 𝑓: 0.23 ( 40894 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.188

Publications

40 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=0.012873054).

BP6

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

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 rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.55T>G	p.Ser19Ala	missense_variant	Exon 2 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 link	c.55T>G	p.Ser19Ala	missense_variant	Exon 2 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.55T>G	p.Ser19Ala	missense_variant	Exon 2 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2 link	c.55T>G	p.Ser19Ala	missense_variant	Exon 2 of 38		NM_001384140.1	ENSP00000495195.1

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

GnomAD2 exomes

AF:

0.221

AC:

55151

AN:

250098

AF XY:

0.218

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 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

African (AFR)

AF:

0.141

AC:

4705

AN:

33388

American (AMR)

AF:

0.287

AC:

12768

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.314

AC:

8182

AN:

26052

East Asian (EAS)

AF:

0.118

AC:

4659

AN:

39628

South Asian (SAS)

AF:

0.149

AC:

12809

AN:

86132

European-Finnish (FIN)

AF:

0.149

AC:

7965

AN:

53338

Middle Eastern (MID)

AF:

0.330

AC:

1902

AN:

5756

European-Non Finnish (NFE)

AF:

0.245

AC:

271437

AN:

1109888

Other (OTH)

AF:

0.229

AC:

13822

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

12685

25370

38054

50739

63424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9080

18160

27240

36320

45400

<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:

0.204

AC:

31010

AN:

151926

Hom.:

3422

Cov.:

AF XY:

0.199

AC XY:

14783

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.140

AC:

5809

AN:

41504

American (AMR)

AF:

0.245

AC:

3726

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

1115

AN:

3462

East Asian (EAS)

AF:

0.127

AC:

653

AN:

5160

South Asian (SAS)

AF:

0.144

AC:

692

AN:

4822

European-Finnish (FIN)

AF:

0.147

AC:

1559

AN:

10590

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.245

AC:

16628

AN:

67854

Other (OTH)

AF:

0.241

AC:

508

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1231

2461

3692

4922

6153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.236

Hom.:

16815

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

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

- -

Jun 23, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

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:4

Apr 25, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Usher syndrome type 1F

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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 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

0.073

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.4

(source)

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;.;.

PhyloP100

-0.19

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

Mutation Taster

=299/1

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