rs41274636

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033056.4(PCDH15):c.157+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 1,603,330 control chromosomes in the GnomAD database, including 5,925 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 Benign (★★).

Frequency

Genomes: 𝑓 0.094 ( 702 hom., cov: 32)

Exomes 𝑓: 0.083 ( 5223 hom. )

Consequence

PCDH15
NM_033056.4 splice_region, intron

Scores

Splicing: ADA: 0.001148

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.746

Publications

9 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:

ENSG00000234173 (HGNC:):

ENSG00000234173 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 (BayesDel_noAF=-0.49).

BP6

Variant 10-54527809-T-C is Benign according to our data. Variant chr10-54527809-T-C is described in ClinVar as [Benign]. Clinvar id is 46444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.157+3A>G		splice_region_variant, intron_variant	Intron 3 of 32	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.157+3A>G		splice_region_variant, intron_variant	Intron 3 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.157+3A>G		splice_region_variant, intron_variant	Intron 3 of 32	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.157+3A>G		splice_region_variant, intron_variant	Intron 3 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.0937

AC:

14225

AN:

151842

Hom.:

696

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0689

Gnomad ASJ

AF:

0.0514

Gnomad EAS

AF:

0.0832

Gnomad SAS

AF:

0.0570

Gnomad FIN

AF:

0.0606

Gnomad MID

AF:

0.0924

Gnomad NFE

AF:

0.0839

Gnomad OTH

AF:

0.0872

GnomAD2 exomes

AF:

0.0782

AC:

19457

AN:

248754

AF XY:

0.0761

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.0646

Gnomad ASJ exome

AF:

0.0501

Gnomad EAS exome

AF:

0.0740

Gnomad FIN exome

AF:

0.0654

Gnomad NFE exome

AF:

0.0860

Gnomad OTH exome

AF:

0.0842

GnomAD4 exome

AF:

0.0827

AC:

120086

AN:

1451368

Hom.:

5223

Cov.:

AF XY:

0.0818

AC XY:

59065

AN XY:

722368

show subpopulations

African (AFR)

AF:

0.141

AC:

4667

AN:

33176

American (AMR)

AF:

0.0662

AC:

2927

AN:

44216

Ashkenazi Jewish (ASJ)

AF:

0.0505

AC:

1310

AN:

25936

East Asian (EAS)

AF:

0.0830

AC:

3285

AN:

39590

South Asian (SAS)

AF:

0.0551

AC:

4693

AN:

85202

European-Finnish (FIN)

AF:

0.0639

AC:

3407

AN:

53302

Middle Eastern (MID)

AF:

0.0827

AC:

474

AN:

5734

European-Non Finnish (NFE)

AF:

0.0853

AC:

94205

AN:

1104228

Other (OTH)

AF:

0.0853

AC:

5118

AN:

59984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

4753

9506

14258

19011

23764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0938

AC:

14252

AN:

151962

Hom.:

702

Cov.:

AF XY:

0.0914

AC XY:

6794

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.138

AC:

5718

AN:

41474

American (AMR)

AF:

0.0687

AC:

1047

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.0514

AC:

178

AN:

3464

East Asian (EAS)

AF:

0.0834

AC:

429

AN:

5142

South Asian (SAS)

AF:

0.0577

AC:

278

AN:

4820

European-Finnish (FIN)

AF:

0.0606

AC:

643

AN:

10608

Middle Eastern (MID)

AF:

0.0890

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0839

AC:

5697

AN:

67894

Other (OTH)

AF:

0.0858

AC:

181

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

637

1274

1912

2549

3186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0878

Hom.:

493

Bravo

AF:

0.0979

Asia WGS

AF:

0.0800

AC:

278

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 08, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1F

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

0.75

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0011

dbscSNV1_RF

Benign

0.034

SpliceAI score (max)

0.010

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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rs41274636

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