rs4935502

Positions:

chr10-54195684-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001384140.1(PCDH15):c.1304A>C(p.Asp435Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,610,574 control chromosomes in the GnomAD database, including 39,899 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D435?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.18 ( 3801 hom., cov: 32)

Exomes 𝑓: 0.18 ( 36098 hom. )

Consequence

PCDH15
NM_001384140.1 missense, splice_region

Scores

Splicing: ADA: 0.9938

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.99

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 -16 ACMG points.

BP6

Variant 10-54195684-T-G is Benign according to our data. Variant chr10-54195684-T-G is described in ClinVar as [Benign]. Clinvar id is 46440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54195684-T-G is described in Lovd as [Benign]. Variant chr10-54195684-T-G is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 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.1304A>C	p.Asp435Ala	missense_variant, splice_region_variant	11/33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 linkuse as main transcript	c.1304A>C	p.Asp435Ala	missense_variant, splice_region_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.1304A>C	p.Asp435Ala	missense_variant, splice_region_variant	11/33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.1304A>C	p.Asp435Ala	missense_variant, splice_region_variant	11/38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26747

AN:

152036

Hom.:

3799

Cov.:

show subpopulations

Gnomad AFR

AF:

0.131

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.212

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.843

Gnomad SAS

AF:

0.370

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.139

Gnomad OTH

AF:

0.176

GnomAD3 exomes

AF:

0.240

AC:

60262

AN:

251270

Hom.:

11768

AF XY:

0.240

AC XY:

32557

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.843

Gnomad SAS exome

AF:

0.349

Gnomad FIN exome

AF:

0.144

Gnomad NFE exome

AF:

0.143

Gnomad OTH exome

AF:

0.208

GnomAD4 exome

AF:

0.178

AC:

258923

AN:

1458420

Hom.:

36098

Cov.:

AF XY:

0.182

AC XY:

132192

AN XY:

725766

show subpopulations

Gnomad4 AFR exome

AF:

0.130

Gnomad4 AMR exome

AF:

0.280

Gnomad4 ASJ exome

AF:

0.139

Gnomad4 EAS exome

AF:

0.870

Gnomad4 SAS exome

AF:

0.341

Gnomad4 FIN exome

AF:

0.146

Gnomad4 NFE exome

AF:

0.138

Gnomad4 OTH exome

AF:

0.202

GnomAD4 genome

AF:

0.176

AC:

26758

AN:

152154

Hom.:

3801

Cov.:

AF XY:

0.186

AC XY:

13838

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.131

Gnomad4 AMR

AF:

0.213

Gnomad4 ASJ

AF:

0.135

Gnomad4 EAS

AF:

0.843

Gnomad4 SAS

AF:

0.369

Gnomad4 FIN

AF:

0.143

Gnomad4 NFE

AF:

0.139

Gnomad4 OTH

AF:

0.180

Alfa

AF:

0.162

Hom.:

7404

Bravo

AF:

0.182

TwinsUK

AF:

0.129

AC:

478

ALSPAC

AF:

0.143

AC:

551

ESP6500AA

AF:

0.131

AC:

579

ESP6500EA

AF:

0.132

AC:

1133

ExAC

AF:

0.238

AC:

28895

Asia WGS

AF:

0.575

AC:

1995

AN:

3478

EpiCase

AF:

0.146

EpiControl

AF:

0.145

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2019	This variant is associated with the following publications: (PMID: 19816713, 27275418, 22815625) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -

Usher syndrome type 1F

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Usher syndrome type 1

Benign:1

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 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;T;D;D;T;T;T;D;T;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0000011

T;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

-1.1

MutationAssessor

Benign

1.7

.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;L;L

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.2

D;.;.;D;.;.;N;.;D;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0090

D;.;.;D;.;.;D;.;T;D;.;D;D;.;T;.;.;D;D;D;.;T;D;D

Sift4G

Uncertain

0.0090

D;.;D;D;D;D;T;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.87, 0.97, 0.88, 0.99, 0.99, 0.95, 0.84

.;.;.;.;.;.;.;.;.;.;.;.;P;.;D;.;.;P;D;D;.;D;P;P

Vest4

0.53

MPC

0.13

ClinPred

0.020

GERP RS

5.1

Varity_R

0.23

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.95

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