rs375855445

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001384140.1(PCDH15):c.2424G>C(p.Lys808Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.282

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057411432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.2424G>C	p.Lys808Asn	missense_variant	Exon 19 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.2424G>C	p.Lys808Asn	missense_variant	Exon 19 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.2424G>C	p.Lys808Asn	missense_variant	Exon 19 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.2424G>C	p.Lys808Asn	missense_variant	Exon 19 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

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:

0.000177

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000191

AC:

AN:

251326

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000781

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:

0.000158

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000161

AC:

236

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000164

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000721

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jul 06, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a cohort of individuals with syndromic and nonsyndromic blindness (PMID: 32483926); patient clinical information not provided; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32483926, 15537665) -

not specified

Uncertain:2

Nov 30, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Oct 28, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F

Uncertain:1

Jan 07, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

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

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.94

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

0.016

MetaRNN

Benign

0.057

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.58

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

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

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

REVEL

Benign

0.074

Sift

Uncertain

0.021

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

Sift4G

Uncertain

0.024

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

Polyphen

0.26, 0.74, 0.18, 0.99, 0.74, 0.045, 0.0040

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

Vest4

0.66

MutPred

0.55

Loss of ubiquitination at K808 (P = 0.0224);Loss of ubiquitination at K808 (P = 0.0224);.;Loss of ubiquitination at K808 (P = 0.0224);Loss of ubiquitination at K808 (P = 0.0224);.;Loss of ubiquitination at K808 (P = 0.0224);.;.;.;Loss of ubiquitination at K808 (P = 0.0224);.;.;.;.;Loss of ubiquitination at K808 (P = 0.0224);Loss of ubiquitination at K808 (P = 0.0224);.;.;.;Loss of ubiquitination at K808 (P = 0.0224);Loss of ubiquitination at K808 (P = 0.0224);

MVP

0.60

MPC

0.039

ClinPred

0.064

GERP RS

2.8

Varity_R

0.11

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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