10-53810587-C-T

Position:

chr10-53810587-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001384140.1(PCDH15):c.4640G>A(p.Gly1547Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00944 in 1,613,770 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 82 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.53

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00866279).

BP6

Variant 10-53810587-C-T is Benign according to our data. Variant chr10-53810587-C-T is described in ClinVar as [Benign]. Clinvar id is 227001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53810587-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00717 (1092/152268) while in subpopulation NFE AF= 0.0107 (727/68016). AF 95% confidence interval is 0.01. There are 11 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1 linkuse as main transcript	c.4640G>A	p.Gly1547Asp	missense_variant	37/38	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.4640G>A	p.Gly1547Asp	missense_variant	37/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.00718

AC:

1092

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.0167

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00767

AC:

1908

AN:

248774

Hom.:

AF XY:

0.00761

AC XY:

1029

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.00588

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.0159

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.00694

GnomAD4 exome

AF:

0.00967

AC:

14138

AN:

1461502

Hom.:

Cov.:

AF XY:

0.00921

AC XY:

6698

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00340

Gnomad4 ASJ exome

AF:

0.00563

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000603

Gnomad4 FIN exome

AF:

0.0152

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00785

GnomAD4 genome

AF:

0.00717

AC:

1092

AN:

152268

Hom.:

Cov.:

AF XY:

0.00729

AC XY:

543

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00530

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0167

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00992

Hom.:

Bravo

AF:

0.00635

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0120

AC:

ExAC

AF:

0.00792

AC:

955

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0103

EpiControl

AF:

0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	PCDH15: BP4, BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Val1508Met in Exon 35B of PCDH15: This variant is not expected to have clinical significance because it has been identified in 1.2% (63/5446) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs41274622). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0074

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

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

D;T;D;D;D;D;D;T;T;T;T

MetaRNN

Benign

0.0087

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

MetaSVM

Benign

-0.96

MutationTaster

Benign

1.0

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

REVEL

Benign

0.094

Sift4G

Benign

0.40

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

Vest4

0.41

MVP

0.46

ClinPred

0.069

GERP RS

4.2

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