Variant rs566386133 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000395445.6(PCDH15):c.4711C>T(p.Arg1571Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PCDH15
ENST00000395445.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.910

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12506449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1 linkuse as main transcript	c.4671+1223C>T		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2 linkuse as main transcript	c.4671+1223C>T		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.0000294

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248588

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135088

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1460972

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000145

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.000340

ExAC

AF:

0.0000332

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 20, 2016

The p.Arg1578Cys variant in PCDH15 has been previously reported in 1 individual with hearing loss by our laboratory; however, a variant affecting the remaining copy of PCDH15 was not identified in this individual. This variant has been iden tified in 2/11518 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs566386133); however, its frequency is no t high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis are limited or unavailable for this variant. In summary, t he clinical significance of the p.Arg1578Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.0029

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

.;.;.;T;.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.85

D;D;D;D;D;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.13

T;T;T;T;T;T

MetaSVM

Uncertain

0.070

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PROVEAN

Benign

-1.9

N;N;N;.;.;.

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;D;D;.;.;.

Sift4G

Uncertain

0.025

D;D;D;D;D;D

Vest4

0.46

MVP

0.65

ClinPred

0.51

GERP RS

3.5

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