chr10-53822367-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033056.4(PCDH15):c.5359C>T(p.Pro1787Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,576,182 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 37 hom., cov: 32)

Exomes 𝑓: 0.016 ( 307 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.06

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=0.0032382607).

BP6

Variant 10-53822367-G-A is Benign according to our data. Variant chr10-53822367-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0152 (2304/151458) while in subpopulation AMR AF = 0.0216 (327/15138). AF 95% confidence interval is 0.0197. There are 37 homozygotes in GnomAd4. There are 1334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.5359C>T	p.Pro1787Ser	missense_variant	Exon 33 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.4368-2137C>T		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.5359C>T	p.Pro1787Ser	missense_variant	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.4368-2137C>T		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2307

AN:

151340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00250

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.0219

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.00585

Gnomad FIN

AF:

0.0747

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.00673

GnomAD2 exomes

AF:

0.0184

AC:

3421

AN:

186126

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.00273

Gnomad AMR exome

AF:

0.0202

Gnomad ASJ exome

AF:

0.00297

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0727

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.0126

GnomAD4 exome

AF:

0.0155

AC:

22153

AN:

1424724

Hom.:

307

Cov.:

AF XY:

0.0153

AC XY:

10770

AN XY:

705728

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

32246

American (AMR)

AF:

0.0202

AC:

773

AN:

38314

Ashkenazi Jewish (ASJ)

AF:

0.00331

AC:

AN:

25702

East Asian (EAS)

AF:

0.0000806

AC:

AN:

37204

South Asian (SAS)

AF:

0.00838

AC:

697

AN:

83194

European-Finnish (FIN)

AF:

0.0688

AC:

3537

AN:

51418

Middle Eastern (MID)

AF:

0.00106

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.0149

AC:

16234

AN:

1091948

Other (OTH)

AF:

0.0127

AC:

749

AN:

59032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1489

2978

4466

5955

7444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

622

1244

1866

2488

3110

<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:

0.0152

AC:

2304

AN:

151458

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1334

AN XY:

73970

show subpopulations

African (AFR)

AF:

0.00249

AC:

103

AN:

41304

American (AMR)

AF:

0.0216

AC:

327

AN:

15138

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3464

East Asian (EAS)

AF:

0.000391

AC:

AN:

5116

South Asian (SAS)

AF:

0.00606

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.0747

AC:

783

AN:

10488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0148

AC:

1002

AN:

67858

Other (OTH)

AF:

0.00666

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

105

210

315

420

525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0123

Hom.:

Bravo

AF:

0.00993

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.0123

AC:

106

ExAC

AF:

0.0128

AC:

1525

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro1787Ser in exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because this residue is not highly conserved across species. Of note , rat has a serine at this position. In addition, computational analyses do not suggest a high likelihood of clinical significance and this variant is listed in dbSNP with a heterozygous frequency over 1% (rs61862390). -

Sep 20, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2013

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. -

not provided

Benign:4

Jul 10, 2019

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

- -

Sep 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Usher syndrome type 1F

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 18, 2014

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Usher syndrome type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.2

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.017

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

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.80

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

MetaRNN

Benign

0.0032

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

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

PhyloP100

2.1

PrimateAI

Benign

0.35

PROVEAN

Benign

0.13

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

REVEL

Benign

0.084

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.29

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

Polyphen

0.015

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

Vest4

0.11

MPC

0.028

ClinPred

0.058

GERP RS

1.7

Varity_R

0.060

gMVP

0.17

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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