rs143570915

Positions:

chr10-54369251-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The ENST00000320301.11(PCDH15):c.343G>A(p.Val115Met) variant causes a missense change. The variant allele was found at a frequency of 0.000326 in 1,612,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V115A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

PCDH15
ENST00000320301.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 6.17

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a domain Cadherin 1 (size 107) in uniprot entity PCD15_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in ENST00000320301.11

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010353655).

BP6

Variant 10-54369251-C-T is Benign according to our data. Variant chr10-54369251-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46467.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00185 (281/152096) while in subpopulation AFR AF= 0.00662 (275/41526). AF 95% confidence interval is 0.00598. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.343G>A	p.Val115Met	missense_variant	5/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 linkuse as main transcript	c.343G>A	p.Val115Met	missense_variant	5/38	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.343G>A	p.Val115Met	missense_variant	5/33	1	NM_033056.4	ENSP00000322604		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.343G>A	p.Val115Met	missense_variant	5/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

281

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00664

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000419

AC:

105

AN:

250630

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

135458

show subpopulations

Gnomad AFR exome

AF:

0.00597

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000167

AC:

244

AN:

1460608

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

726592

show subpopulations

Gnomad4 AFR exome

AF:

0.00574

Gnomad4 AMR exome

AF:

0.000404

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.00185

AC:

281

AN:

152096

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00662

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000317

Hom.:

Bravo

AF:

0.00188

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000519

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2015	p.Val115Met in exon 5 of PCDH15: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (60/10352) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org, dbSNP rs143570915). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 03, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.343G>A (p.V115M) alteration is located in exon 5 (coding exon 4) of the PCDH15 gene. This alteration results from a G to A substitution at nucleotide position 343, causing the valine (V) at amino acid position 115 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PCDH15-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.035

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

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.010

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

-0.46

MutationAssessor

Benign

1.0

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.2

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

REVEL

Benign

0.28

Sift

Uncertain

0.0010

D;.;.;.;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D

Sift4G

Pathogenic

0.0

D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0

.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D

Vest4

0.86

MVP

0.66

MPC

0.22

ClinPred

0.069

GERP RS

5.5

Varity_R

0.35

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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