rs111033516

Positions:

chr10-54020318-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The ENST00000320301.11(PCDH15):c.2625G>A(p.Ser875=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00553 in 1,613,736 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S875S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 36 hom. )

Consequence

PCDH15
ENST00000320301.11 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -1.33

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 10-54020318-C-T is Benign according to our data. Variant chr10-54020318-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46454.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=4}. Variant chr10-54020318-C-T is described in Lovd as [Benign]. Variant chr10-54020318-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.33 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00387 (588/152092) while in subpopulation NFE AF= 0.00631 (429/67948). AF 95% confidence interval is 0.00582. There are 6 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.2625G>A	p.Ser875=	synonymous_variant	20/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 linkuse as main transcript	c.2625G>A	p.Ser875=	synonymous_variant	20/38	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.2625G>A	p.Ser875=	synonymous_variant	20/33	1	NM_033056.4	ENSP00000322604		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.2625G>A	p.Ser875=	synonymous_variant	20/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.00388

AC:

589

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00440

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00633

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00345

AC:

866

AN:

251258

Hom.:

AF XY:

0.00337

AC XY:

457

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00208

Gnomad NFE exome

AF:

0.00584

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00571

AC:

8344

AN:

1461644

Hom.:

Cov.:

AF XY:

0.00549

AC XY:

3993

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00313

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00232

Gnomad4 NFE exome

AF:

0.00696

Gnomad4 OTH exome

AF:

0.00460

GnomAD4 genome

AF:

0.00387

AC:

588

AN:

152092

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

266

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.00440

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00631

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00469

Hom.:

Bravo

AF:

0.00377

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00535

EpiControl

AF:

0.00616

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 15, 2012	Ser875Ser in exon 20 of PCDH15: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, has been identified in 0.5% (38/7020) of Europe an American chromosomes and 0.1% (5/3736) of African American chromosomes from a broad population by the NHLBI Exome sequencing project (http://evs.gs.washingto n.edu/EVS/; dbSNP rs111033516). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Usher syndrome type 1F

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PCDH15: BP4, BP7, BS2 -

Usher syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.6

DANN

Benign

0.58

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