rs1268531021

Positions:

Variant summary

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

The NM_033056.4(PCDH15):c.5372C>T(p.Pro1791Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000443 in 1,579,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.66

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=0.09172252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.5372C>T	p.Pro1791Leu	missense_variant	33/33	ENST00000320301.11
PCDH15	NM_001384140.1 linkuse as main transcript	c.4368-2124C>T		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.5372C>T	p.Pro1791Leu	missense_variant	33/33	1	NM_033056.4		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.4368-2124C>T		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151478

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000104

AC:

AN:

191604

Hom.:

AF XY:

0.0000194

AC XY:

AN XY:

102950

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000420

AC:

AN:

1428102

Hom.:

Cov.:

AF XY:

0.00000565

AC XY:

AN XY:

707740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000549

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151478

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73986

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 28, 2016

The p.Pro1791Leu variant in PCDH15 has been previously reported in the heterozyg ous state in one individual with hearing loss, but a variant affecting the remai ning copy of the gene was not identified. It has not been identified in large po pulation studies. Computational prediction tools and conservation analysis sugge st that the p.Pro1791Leu variant may not impact the protein, though this informa tion is not predictive enough to rule out pathogenicity. In summary, the clinica l significance of the p.Pro1791Leu variant is uncertain. -

Usher syndrome type 1F

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 09, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 01, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1791 of the PCDH15 protein (p.Pro1791Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 505142). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.42

CADD

Benign

2.1

DANN

Benign

0.11

DEOGEN2

Benign

0.0083

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

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.092

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

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

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.74

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

REVEL

Benign

0.062

Sift

Uncertain

0.0090

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

Sift4G

Uncertain

0.014

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

Polyphen

0.099

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

Vest4

0.26

MutPred

0.14

.;.;.;Loss of glycosylation at P1793 (P = 0.0207);.;.;.;.;.;

MVP

0.47

MPC

0.028

ClinPred

0.13

GERP RS

1.6

Varity_R

0.033

gMVP

0.24

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