10-53822433-GAGGAGCAGGAGC-GAGGAGC

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_033056.4(PCDH15):c.5287_5292delGCTCCT(p.Ala1763_Pro1764del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000768 in 1,588,994 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 2 hom. )

Consequence

PCDH15
NM_033056.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: 4.46

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 -9 ACMG points.

BP6

Variant 10-53822433-GAGGAGC-G is Benign according to our data. Variant chr10-53822433-GAGGAGC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46493.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4}. Variant chr10-53822433-GAGGAGC-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00101 (152/151192) while in subpopulation EAS AF= 0.00854 (44/5154). AF 95% confidence interval is 0.00654. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.5287_5292delGCTCCT	p.Ala1763_Pro1764del	conservative_inframe_deletion	Exon 33 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.4368-2209_4368-2204delGCTCCT		intron_variant	Intron 32 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.5287_5292delGCTCCT	p.Ala1763_Pro1764del	conservative_inframe_deletion	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.4368-2209_4368-2204delGCTCCT		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

152

AN:

151074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000922

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00852

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000621

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.00103

AC:

216

AN:

209224

Hom.:

AF XY:

0.000977

AC XY:

111

AN XY:

113556

show subpopulations

Gnomad AFR exome

AF:

0.00121

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000107

Gnomad EAS exome

AF:

0.00503

Gnomad SAS exome

AF:

0.000969

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.000917

GnomAD4 exome

AF:

0.000743

AC:

1068

AN:

1437802

Hom.:

AF XY:

0.000774

AC XY:

552

AN XY:

713558

show subpopulations

Gnomad4 AFR exome

AF:

0.00112

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.0000774

Gnomad4 EAS exome

AF:

0.00472

Gnomad4 SAS exome

AF:

0.00113

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.000570

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00101

AC:

152

AN:

151192

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

73940

show subpopulations

Gnomad4 AFR

AF:

0.000999

Gnomad4 AMR

AF:

0.000921

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00854

Gnomad4 SAS

AF:

0.00167

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000621

Gnomad4 OTH

AF:

0.000476

Bravo

AF:

0.00105

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Apr 13, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25307757, 26047050, 33576794, 33111339) -

Jul 02, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCDH15: PM4, BS1:Supporting -

Usher syndrome type 1F

Benign:2

Apr 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1D

Uncertain:1

Oct 01, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_033056.3(PCDH15):c.5287_5292del6(A1763_P1764del) is an in-frame deletion classified as a variant of uncertain significance in the context of PCDH15-related disorders. A1763_P1764del has been observed in cases with relevant disease (PMID: 25830873, 27792758). Functional assessments of this variant are not available in the literature. A1763_P1764del has been observed in population frequency databases (gnomAD: EAS 0.57%). In summary, there is insufficient evidence to classify NM_033056.3(PCDH15):c.5287_5292del6(A1763_P1764del) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Hearing loss, autosomal recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa-deafness syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Apr 14, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala1763_Pro1764del in exon 33 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.8% (18/2306) of East A sian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs397517465). This variant leads to a two codon in-frame delet ion located in the last exon of the gene; however, one study suggests that exon 33 is more tolerant of variation, including truncating variants (Perrault-Micale 2014). -

PCDH15-related disorder

Benign:1

Dec 30, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

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