rs111033463

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033056.4(PCDH15):c.5398G>A(p.Val1800Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000947 in 1,597,250 control chromosomes in the GnomAD database, including 15 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 0.00070 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 14 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.93

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:

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=0.0047968924).

BP6

Variant 10-53822328-C-T is Benign according to our data. Variant chr10-53822328-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53822328-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000972 (1407/1447634) while in subpopulation SAS AF= 0.00705 (601/85220). AF 95% confidence interval is 0.00659. There are 14 homozygotes in gnomad4_exome. There are 892 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 14 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.5398G>A	p.Val1800Ile	missense_variant	Exon 33 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.4368-2098G>A		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.5398G>A	p.Val1800Ile	missense_variant	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.4368-2098G>A		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.000702

AC:

105

AN:

149500

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000222

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.000335

Gnomad ASJ

AF:

0.00318

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00466

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000770

Gnomad OTH

AF:

0.00197

GnomAD3 exomes

AF:

0.00138

AC:

304

AN:

221008

Hom.:

AF XY:

0.00177

AC XY:

211

AN XY:

119246

show subpopulations

Gnomad AFR exome

AF:

0.000488

Gnomad AMR exome

AF:

0.000259

Gnomad ASJ exome

AF:

0.00290

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00628

Gnomad FIN exome

AF:

0.0000484

Gnomad NFE exome

AF:

0.000728

Gnomad OTH exome

AF:

0.00160

GnomAD4 exome

AF:

0.000972

AC:

1407

AN:

1447634

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

892

AN XY:

718994

show subpopulations

Gnomad4 AFR exome

AF:

0.000272

Gnomad4 AMR exome

AF:

0.000286

Gnomad4 ASJ exome

AF:

0.00323

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00705

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.000555

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.000702

AC:

105

AN:

149616

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

AN XY:

72780

show subpopulations

Gnomad4 AFR

AF:

0.000222

Gnomad4 AMR

AF:

0.000335

Gnomad4 ASJ

AF:

0.00318

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00466

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000770

Gnomad4 OTH

AF:

0.00195

Alfa

AF:

0.000922

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00128

AC:

154

Asia WGS

AF:

0.00173

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 provided

Benign:6

Likely 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	GeneDx	May 15, 2020	This variant is associated with the following publications: (PMID: 27984600, 22135276) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 03, 2015	Val1800Ile in exon 33 of PCDH15: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (94/13018) of South Asian chr omosomes, including 1 homozygote, by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs111033463). In addition, the valine (Val) residue at position 1800 is not conserved in several species, with chimpanzee an d macaque having an isoleucine (Ile) at this position. -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -

Usher syndrome type 1F

Benign:2

Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 21, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 13, 2020	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2022

- -

PCDH15-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Usher syndrome type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0040

DANN

Benign

0.55

DEOGEN2

Benign

0.0095

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

Eigen

Benign

-2.7

Eigen_PC

Benign

-2.8

FATHMM_MKL

Benign

0.0093

LIST_S2

Benign

0.61

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

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0048

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

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

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.070

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

REVEL

Benign

0.0070

Sift

Benign

0.70

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

Sift4G

Benign

0.57

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

Polyphen

0.0020

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

Vest4

0.029

MVP

0.19

MPC

0.025

ClinPred

0.00064

GERP RS

-7.5

Varity_R

0.022

gMVP

0.049

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