rs372184022

Positions:

chr10-53809201-T-C

Variant summary

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

The ENST00000395445.6(PCDH15):c.4843A>G(p.Ser1615Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict 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: 0.00017 ( 0 hom. )

Consequence

PCDH15
ENST00000395445.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.51

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2859212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1 linkuse as main transcript	c.4671+1355A>G		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2 linkuse as main transcript	c.4671+1355A>G		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000965

AC:

AN:

248706

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.000204

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000171

AC:

250

AN:

1461666

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

133

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000211

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000112

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000914

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000558

AC:

ExAC

AF:

0.0000665

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Feb 12, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Ser1622Gly va riant in PCDH15 has been previously identified by our laboratory in the heterozy gous state in one child with sensorineural hearing loss, who has a homozygous pa thogenic variant in another gene that explains the hearing loss. The p.Ser1622Gl y variant has also been identified in 8/67250 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs372184022) . Computational prediction tools and conservation analysis suggest that this var iant may not impact the protein, though this information is not predictive enoug h to rule out pathogenicity. In summary, while the clinical significance of the p.Ser1622Gly variant is uncertain, these data suggest that it is more likely to be benign. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The c.4864A>G (p.S1622G) alteration is located in exon 37 (coding exon 36) of the PCDH15 gene. This alteration results from a A to G substitution at nucleotide position 4864, causing the serine (S) at amino acid position 1622 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Usher syndrome type 1D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 16, 2019

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3,BP1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

.;.;.;T;.;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.68

T;T;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.29

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

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

PROVEAN

Benign

-1.5

N;N;N;.;.;.

REVEL

Benign

0.067

Sift

Uncertain

0.014

D;D;D;.;.;.

Sift4G

Uncertain

0.042

D;T;T;T;T;T

Vest4

0.59

MVP

0.50

ClinPred

0.13

GERP RS

5.7

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