rs192813057

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_033056.4(PCDH15):c.2290C>T(p.Arg764Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,613,762 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R764H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 1 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 1.56

Publications

9 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.120475024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.2290C>T	p.Arg764Cys	missense_variant	Exon 19 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.2290C>T	p.Arg764Cys	missense_variant	Exon 19 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.2290C>T	p.Arg764Cys	missense_variant	Exon 19 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.2290C>T	p.Arg764Cys	missense_variant	Exon 19 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.000382

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000367

AC:

AN:

250880

AF XY:

0.000361

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000626

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000692

AC:

1012

AN:

1461640

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

488

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000209

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000837

AC:

931

AN:

1111862

Other (OTH)

AF:

0.000861

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000381

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41526

American (AMR)

AF:

0.0000656

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

67990

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000546

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 11, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Apr 01, 2022

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

Jan 15, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg764Cys variant in PCDH15 has been previously identified by our laborato ry in two individuals with hearing loss; however a variant affecting the remaini ng copy of PCDH15 was not identified in either of them. This variant has been i dentified in 50/66626 (0.08%) of European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs192813057). Although th is variant has been seen in the general population, its frequency is not high en ough to rule out a pathogenic role. Computational prediction tools and conservat ion analyses do not provide strong support for or against an impact to the prote in. In summary, the clinical significance of the p.Arg764Cys variant is uncertai n. -

May 04, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PCDH15 c.2290C>T (p.Arg764Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 250880 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (0.00037 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2290C>T in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=5) and Benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F

Uncertain:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Usher syndrome type 1F

Uncertain:1

Apr 17, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Usher syndrome type 1

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

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

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.12

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

MetaSVM

Benign

-0.60

MutationAssessor

Benign

2.0

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

PhyloP100

1.6

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.9

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

REVEL

Benign

0.21

Sift

Uncertain

0.022

.;.;.;.;.;.;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;T

Sift4G

Uncertain

0.025

D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T

Polyphen

0.99, 1.0, 0.99, 1.0, 0.95

.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;P

Vest4

0.68

MVP

0.79

MPC

0.20

ClinPred

0.089

GERP RS

4.8

Varity_R

0.21

gMVP

0.53

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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