rs184144118

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_033056.4(PCDH15):c.3502-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 1,557,730 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0054 ( 34 hom. )

Consequence

PCDH15
NM_033056.4 splice_region, intron

Scores

Splicing: ADA: 0.00003810

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: -0.109

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 23
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

PCDH15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 10-53866865-G-A is Benign according to our data. Variant chr10-53866865-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46469.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00407 (558/136958) while in subpopulation NFE AF = 0.00538 (355/65964). AF 95% confidence interval is 0.00492. There are 1 homozygotes in GnomAd4. There are 242 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.3502-8C>T		splice_region_variant, intron_variant	Intron 26 of 32	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.3502-8C>T		splice_region_variant, intron_variant	Intron 26 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.3502-8C>T		splice_region_variant, intron_variant	Intron 26 of 32	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.3502-8C>T		splice_region_variant, intron_variant	Intron 26 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.00408

AC:

558

AN:

136852

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00525

Gnomad ASJ

AF:

0.00859

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00164

Gnomad MID

AF:

0.0129

Gnomad NFE

AF:

0.00538

Gnomad OTH

AF:

0.0111

GnomAD2 exomes

AF:

0.00443

AC:

1069

AN:

241144

AF XY:

0.00432

show subpopulations

Gnomad AFR exome

AF:

0.000771

Gnomad AMR exome

AF:

0.00507

Gnomad ASJ exome

AF:

0.00819

Gnomad EAS exome

AF:

0.0000649

Gnomad FIN exome

AF:

0.00175

Gnomad NFE exome

AF:

0.00614

Gnomad OTH exome

AF:

0.00765

GnomAD4 exome

AF:

0.00544

AC:

7734

AN:

1420772

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

3774

AN XY:

709346

show subpopulations

African (AFR)

AF:

0.00133

AC:

AN:

32384

American (AMR)

AF:

0.00541

AC:

238

AN:

44000

Ashkenazi Jewish (ASJ)

AF:

0.00729

AC:

188

AN:

25794

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39432

South Asian (SAS)

AF:

0.00144

AC:

123

AN:

85162

European-Finnish (FIN)

AF:

0.00222

AC:

118

AN:

53262

Middle Eastern (MID)

AF:

0.0127

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00610

AC:

6569

AN:

1076138

Other (OTH)

AF:

0.00648

AC:

382

AN:

58924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

355

710

1065

1420

1775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00407

AC:

558

AN:

136958

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

242

AN XY:

66348

show subpopulations

African (AFR)

AF:

0.00162

AC:

AN:

35084

American (AMR)

AF:

0.00524

AC:

AN:

13538

Ashkenazi Jewish (ASJ)

AF:

0.00859

AC:

AN:

3376

East Asian (EAS)

AF:

0.00

AC:

AN:

2148

South Asian (SAS)

AF:

0.00124

AC:

AN:

4018

European-Finnish (FIN)

AF:

0.00164

AC:

AN:

9772

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00538

AC:

355

AN:

65964

Other (OTH)

AF:

0.0109

AC:

AN:

1918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00434

Hom.:

Bravo

AF:

0.00447

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Feb 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCDH15: BP4, BS2 -

Feb 11, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

3502-8C>T in Intron 26 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.7% (52/7020) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS). -

Jan 22, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PCDH15 c.3502-8C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1152/262912 control chromosomes (6 homozygotes), predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.008337 (83/9956). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic PCDH15 variant (0.0031623), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. The variant of interest has been reported in a study cohort of UK Usher patients, and was classified by authors as neutral (Le Quesne Stabej_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Jan 02, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

PCDH15-related disorder

Benign:1

Apr 20, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Usher syndrome type 1F

Benign:1

Oct 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.21

(source)

DANN

Benign

0.31

PhyloP100

-0.11

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000038

dbscSNV1_RF

Benign

0.0

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

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rs184144118

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over