NM_033056.4:c.5601_5603delAAC

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBA1

The NM_033056.4(PCDH15):c.5601_5603delAAC(p.Thr1868del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,613,894 control chromosomes in the GnomAD database, including 347 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1867T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 175 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 172 hom. )

Consequence

PCDH15
NM_033056.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:2B:10O:1

Conservation

PhyloP100: 2.86

Publications

5 publications found

Variant links:

COSMIC-nc: COSV100225657

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 -15 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_033056.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 10-53822122-CGTT-C is Benign according to our data. Variant chr10-53822122-CGTT-C is described in ClinVar as Benign. ClinVar VariationId is 46505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.5601_5603delAAC	p.Thr1868del	disruptive_inframe_deletion	Exon 33 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.4368-1895_4368-1893delAAC		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.5601_5603delAAC	p.Thr1868del	disruptive_inframe_deletion	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.4368-1895_4368-1893delAAC		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.0258

AC:

3918

AN:

151976

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0865

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.0221

GnomAD2 exomes

AF:

0.00720

AC:

1811

AN:

251400

AF XY:

0.00521

show subpopulations

Gnomad AFR exome

AF:

0.0879

Gnomad AMR exome

AF:

0.00601

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.000915

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00334

AC:

4877

AN:

1461800

Hom.:

172

AF XY:

0.00293

AC XY:

2134

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.0913

AC:

3056

AN:

33474

American (AMR)

AF:

0.00664

AC:

297

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00172

AC:

AN:

26134

East Asian (EAS)

AF:

0.000202

AC:

AN:

39698

South Asian (SAS)

AF:

0.000673

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00780

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000774

AC:

861

AN:

1111948

Other (OTH)

AF:

0.00773

AC:

467

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

313

627

940

1254

1567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.0259

AC:

3945

AN:

152094

Hom.:

175

Cov.:

AF XY:

0.0257

AC XY:

1909

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0869

AC:

3602

AN:

41444

American (AMR)

AF:

0.0136

AC:

208

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3466

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68012

Other (OTH)

AF:

0.0218

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

169

338

507

676

845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0138

Hom.:

Bravo

AF:

0.0301

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Pathogenic:2Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 17, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr1869del in exon 33 of PCDH15: This variant has been reported in 4 individuals with Usher syndrome and one individual with hearing loss, and was absent in 100 control chromosomes (Ouyang 2005, Zheng 2005, Bonnet 2011). However, three of t he Usher syndrome probands did not have a second PCDH15 variant identified, incl uding two probands who had pathogenic variants in another gene. The fourth Usher syndrome proband carried the variant in the compound heterozygous state with an other PCDH15 variant which we feel does not have evidence for pathogenicity. The proband with hearing loss carried this variant in the homozygous state; this is inconsistent with the phenotype expected of two pathogenic PCDH15 variants. Thi s variant has also been identified by our laboratory in two probands, both of wh om carry pathogenic or likely pathogenic variants in other genes. Furthermore, G ET-Evidence database (http://evidence.personalgenomes.org) reports this variant at a frequency of 6% (8/128 chromosomes). In summary, based upon the observation s to date, we feel this variant is likely benign. -

Dec 17, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 18, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PCDH15 c.5601_5603delAAC (p.Thr1869del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0072 in 251400 control chromosomes, predominantly at a frequency of 0.088 within the African or African-American subpopulation in the gnomAD database, including 72 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although cited in the literature, to our knowledge, no occurrence of c.5601_5603delAAC in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1F

Pathogenic:1Benign:1

Mar 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 13, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

USHER SYNDROME, TYPE ID/F, DIGENIC

Pathogenic:1

Mar 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F

Benign:1

Apr 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Mutation Taster

=85/15

polymorphism (auto)

(source)

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

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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