rs199537178

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001384140.1(PCDH15):c.2102C>T(p.Ala701Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,613,056 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 8.75

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21823272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.2102C>T	p.Ala701Val	missense_variant	18/33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 linkuse as main transcript	c.2102C>T	p.Ala701Val	missense_variant	18/38	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.2102C>T	p.Ala701Val	missense_variant	18/33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.2102C>T	p.Ala701Val	missense_variant	18/38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

250958

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000264

AC:

385

AN:

1460938

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

181

AN XY:

726802

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000324

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000112

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000275

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 27, 2021	- -
Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Apr 07, 2015	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 701 of the PCDH15 protein (p.Ala701Val). This variant is present in population databases (rs199537178, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 164921). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCDH15 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported without a second PCDH15 variant in a proband with bilateral sensorineural hearing loss who also had multiple variants in other hearing loss-associated genes (PMID: 29907799); This variant is associated with the following publications: (PMID: 15537665, 29907799) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 07, 2015

The p.Ala701Val variant in PCDH15 has been previously reported by our laboratory in one individual with mild to moderate sensorineural hearing loss; however, a second variant affecting the remaining copy of PCDH15 was not identified in that individual (LMM unpublished data). This variant has been identified in 13/6654 8 European chromosomes by the Exome Aggregation consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs199537178). Computational prediction tools and conserv ation analysis do not provide strong support for or against an impact to the pro tein. In summary, the clinical significance of the p.Ala701Val variant is uncert ain. -

Usher syndrome type 1F

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

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

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

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

0.028

MetaRNN

Benign

0.22

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

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.080

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

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.5

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

REVEL

Benign

0.29

Sift

Benign

0.041

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

Sift4G

Uncertain

0.031

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

Polyphen

0.20, 0.88, 0.77, 0.98, 0.77, 0.17

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

Vest4

0.54

MVP

0.72

MPC

0.093

ClinPred

0.39

GERP RS

4.9

Varity_R

0.30

gMVP

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