rs145418788

Positions:

chr10-53809447-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_001384140.1(PCDH15):c.4671+1109C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,613,888 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

PCDH15
NM_001384140.1 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.79

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 Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0037893653).

BP6

Variant 10-53809447-G-A is Benign according to our data. Variant chr10-53809447-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00187 (285/152204) while in subpopulation AFR AF= 0.0066 (274/41524). AF 95% confidence interval is 0.00596. There are 0 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1 linkuse as main transcript	c.4671+1109C>T		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+1109C>T		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

282

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.000478

GnomAD3 exomes

AF:

0.000386

AC:

AN:

248792

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.00590

Gnomad AMR exome

AF:

0.0000869

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:

0.00000888

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461684

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00591

Gnomad4 AMR exome

AF:

0.0000894

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:

0.00000180

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.00187

AC:

285

AN:

152204

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00660

Gnomad4 AMR

AF:

0.000589

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:

0.000473

Alfa

AF:

0.000363

Hom.:

Bravo

AF:

0.00207

ESP6500AA

AF:

0.00542

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000498

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2016	Pro1540Ser in Exon 37A of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.6% (59/9740) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145418788). -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PCDH15: BP4, BS2 -

PCDH15-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0026

.;.;.;T;.;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.81

T;T;T;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.0038

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

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

PROVEAN

Benign

-0.80

N;N;D;.;.;.

REVEL

Benign

0.074

Sift

Benign

0.030

D;D;D;.;.;.

Sift4G

Benign

0.24

T;T;T;T;T;T

Vest4

0.39

MVP

0.49

ClinPred

0.0063

GERP RS

4.9

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