rs61862390

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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:

PCDH15 (HGNC:):

PCDH15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 46498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53822367-G-A is described in Lovd as [Benign]. Variant chr10-53822367-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 37 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.5359C>T	p.Pro1787Ser	missense_variant	33/33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 linkuse as main transcript	c.4368-2137C>T		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.5359C>T	p.Pro1787Ser	missense_variant	33/33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.4368-2137C>T		intron_variant			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

GnomAD3 exomes

AF:

0.0184

AC:

3421

AN:

186126

Hom.:

AF XY:

0.0173

AC XY:

1734

AN XY:

99994

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 SAS exome

AF:

0.00809

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

Gnomad4 AFR exome

AF:

0.00214

Gnomad4 AMR exome

AF:

0.0202

Gnomad4 ASJ exome

AF:

0.00331

Gnomad4 EAS exome

AF:

0.0000806

Gnomad4 SAS exome

AF:

0.00838

Gnomad4 FIN exome

AF:

0.0688

Gnomad4 NFE exome

AF:

0.0149

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.0152

AC:

2304

AN:

151458

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1334

AN XY:

73970

show subpopulations

Gnomad4 AFR

AF:

0.00249

Gnomad4 AMR

AF:

0.0216

Gnomad4 ASJ

AF:

0.00433

Gnomad4 EAS

AF:

0.000391

Gnomad4 SAS

AF:

0.00606

Gnomad4 FIN

AF:

0.0747

Gnomad4 NFE

AF:

0.0148

Gnomad4 OTH

AF:

0.00666

Alfa

AF:

0.0125

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 29, 2011	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2013	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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 1F

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 18, 2014	- -

Usher syndrome type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

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

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