10-53810587-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 9/14 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 was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001384140.1 link	c.4640G>A	p.Gly1547Asp	missense_variant	Exon 37 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2 link	c.4640G>A	p.Gly1547Asp	missense_variant	Exon 37 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

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

GnomAD2 exomes

AF:

0.00767

AC:

1908

AN:

248774

AF XY:

0.00761

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 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

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.00340

AC:

152

AN:

44724

Gnomad4 ASJ exome

AF:

0.00563

AC:

147

AN:

26130

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39684

Gnomad4 SAS exome

AF:

0.000603

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.0152

AC:

811

AN:

53336

Gnomad4 NFE exome

AF:

0.0112

AC:

12420

AN:

1111756

Gnomad4 Remaining exome

AF:

0.00785

AC:

474

AN:

60370

Heterozygous variant carriers

732

1464

2196

2928

3660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.0017092

AN:

0.0017092

Gnomad4 AMR

AF:

0.00530

AC:

0.0052955

AN:

0.0052955

Gnomad4 ASJ

AF:

0.00518

AC:

0.00518433

AN:

0.00518433

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000621

AC:

0.000620604

AN:

0.000620604

Gnomad4 FIN

AF:

0.0167

AC:

0.0166887

AN:

0.0166887

Gnomad4 NFE

AF:

0.0107

AC:

0.0106887

AN:

0.0106887

Gnomad4 OTH

AF:

0.00616

AC:

0.0061553

AN:

0.0061553

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00958

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

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCDH15: BP4, BS1, BS2 -

Apr 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 16, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

Mutation Taster

=89/11

polymorphism

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