rs10825269

Positions:

chr10-54195850-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033056.4(PCDH15):c.1138G>A(p.Gly380Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,612,490 control chromosomes in the GnomAD database, including 22,139 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 5424 hom., cov: 32)

Exomes 𝑓: 0.14 ( 16715 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 2.78

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=0.0051817894).

BP6

Variant 10-54195850-C-T is Benign according to our data. Variant chr10-54195850-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54195850-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.1138G>A	p.Gly380Ser	missense_variant	11/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 linkuse as main transcript	c.1138G>A	p.Gly380Ser	missense_variant	11/38	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.1138G>A	p.Gly380Ser	missense_variant	11/33	1	NM_033056.4	ENSP00000322604		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.1138G>A	p.Gly380Ser	missense_variant	11/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33582

AN:

151810

Hom.:

5410

Cov.:

show subpopulations

Gnomad AFR

AF:

0.457

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.116

Gnomad EAS

AF:

0.0907

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.196

GnomAD3 exomes

AF:

0.162

AC:

40803

AN:

251322

Hom.:

4357

AF XY:

0.156

AC XY:

21203

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.459

Gnomad AMR exome

AF:

0.209

Gnomad ASJ exome

AF:

0.118

Gnomad EAS exome

AF:

0.0950

Gnomad SAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.156

GnomAD4 exome

AF:

0.138

AC:

202015

AN:

1460562

Hom.:

16715

Cov.:

AF XY:

0.138

AC XY:

99944

AN XY:

726670

show subpopulations

Gnomad4 AFR exome

AF:

0.470

Gnomad4 AMR exome

AF:

0.210

Gnomad4 ASJ exome

AF:

0.118

Gnomad4 EAS exome

AF:

0.0668

Gnomad4 SAS exome

AF:

0.179

Gnomad4 FIN exome

AF:

0.113

Gnomad4 NFE exome

AF:

0.126

Gnomad4 OTH exome

AF:

0.153

GnomAD4 genome

AF:

0.221

AC:

33633

AN:

151928

Hom.:

5424

Cov.:

AF XY:

0.218

AC XY:

16176

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.457

Gnomad4 AMR

AF:

0.196

Gnomad4 ASJ

AF:

0.116

Gnomad4 EAS

AF:

0.0907

Gnomad4 SAS

AF:

0.180

Gnomad4 FIN

AF:

0.108

Gnomad4 NFE

AF:

0.122

Gnomad4 OTH

AF:

0.198

Alfa

AF:

0.142

Hom.:

4832

Bravo

AF:

0.242

TwinsUK

AF:

0.132

AC:

488

ALSPAC

AF:

0.135

AC:

521

ESP6500AA

AF:

0.442

AC:

1947

ESP6500EA

AF:

0.128

AC:

1101

ExAC

AF:

0.166

AC:

20100

Asia WGS

AF:

0.159

AC:

554

AN:

3478

EpiCase

AF:

0.129

EpiControl

AF:

0.124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 21569298, 19816713) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Usher syndrome type 1F

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 13, 2022

- -

Usher syndrome type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.0021

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

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.66

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

MetaRNN

Benign

0.0052

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.81

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

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P

PrimateAI

Uncertain

0.50

PROVEAN

Benign

1.8

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

REVEL

Benign

0.054

Sift

Benign

1.0

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

Sift4G

Benign

0.59

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

Polyphen

0.0, 0.0070, 0.0040, 0.017

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

Vest4

0.053

MPC

0.028

ClinPred

0.014

GERP RS

5.2

Varity_R

0.10

gMVP

0.15

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