10-53807001-C-T

Position:

chr10-53807001-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001384140.1(PCDH15):c.4801G>A(p.Gly1601Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000243 in 1,613,482 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 4.77

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009886026).

BP6

Variant 10-53807001-C-T is Benign according to our data. Variant chr10-53807001-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227836.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1 linkuse as main transcript	c.4801G>A	p.Gly1601Ser	missense_variant	38/38	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.4801G>A	p.Gly1601Ser	missense_variant	38/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00431

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000722

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:

0.000958

GnomAD3 exomes

AF:

0.000326

AC:

AN:

248194

Hom.:

AF XY:

0.000230

AC XY:

AN XY:

134822

show subpopulations

Gnomad AFR exome

AF:

0.00428

Gnomad AMR exome

AF:

0.000349

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:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000137

AC:

200

AN:

1461450

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.00460

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.00126

AC:

192

AN:

152032

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00429

Gnomad4 AMR

AF:

0.000722

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:

0.000948

Alfa

AF:

0.000392

Hom.:

Bravo

AF:

0.00166

ESP6500AA

AF:

0.00542

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000365

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2017	The G1543S variant in the PCDH15 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G1543S variant is observed in 37/9726 (0.38%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The G1543S variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G1543S as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2015	p.Gly1543Ser in Exon 36C of PCDH15: This variant is not expected to have clinica l significance because it has been identified in 0.4% (37/9726) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs181306086). -

PCDH15-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

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

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

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

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.0071

MetaRNN

Benign

0.0099

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

MetaSVM

Uncertain

-0.24

MutationTaster

Benign

0.98

D;D

REVEL

Benign

0.25

Sift4G

Benign

0.25

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

Vest4

0.20

MVP

0.78

ClinPred

0.054

GERP RS

5.9

Splicing

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