Variant rs562377533 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_033056.4(PCDH15):c.734G>T(p.Arg245Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,461,680 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R245Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30354416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.734G>T	p.Arg245Leu	missense_variant	8/33	ENST00000320301.11
PCDH15	NM_001384140.1 linkuse as main transcript	c.734G>T	p.Arg245Leu	missense_variant	8/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.734G>T	p.Arg245Leu	missense_variant	8/33	1	NM_033056.4		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.734G>T	p.Arg245Leu	missense_variant	8/38		NM_001384140.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251126

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135738

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461680

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727142

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:

0.0000369

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2022

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 245 of the PCDH15 protein (p.Arg245Leu). This variant is present in population databases (rs562377533, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. 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: "Possibly Damaging"; 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

Pathogenic

0.77

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Benign

0.77

DEOGEN2

Benign

0.017

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

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

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

Uncertain

0.089

MetaRNN

Benign

0.30

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

-0.75

MutationAssessor

Benign

-1.6

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.7

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

REVEL

Benign

0.23

Sift

Benign

0.34

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

Sift4G

Uncertain

0.058

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

Polyphen

0.12, 0.34, 0.39, 1.0, 1.0, 0.20, 0.0020

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

Vest4

0.38

MutPred

0.59

Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;.;.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);.;.;Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);Loss of phosphorylation at T248 (P = 0.0478);

MVP

0.74

MPC

0.14

ClinPred

0.62

GERP RS

4.8

Varity_R

0.30

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

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