10-53823145-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_033056.4(PCDH15):c.4581C>A(p.Pro1527Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,698 control chromosomes in the GnomAD database, including 23,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1527P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.14 ( 2810 hom., cov: 32)

Exomes 𝑓: 0.097 ( 20282 hom. )

Consequence

PCDH15
NM_033056.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.456

Publications

24 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 10-53823145-G-T is Benign according to our data. Variant chr10-53823145-G-T is described in ClinVar as Benign. ClinVar VariationId is 46482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.456 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.4581C>A	p.Pro1527Pro	synonymous_variant	Exon 33 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.4368-2915C>A		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.4581C>A	p.Pro1527Pro	synonymous_variant	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.4368-2915C>A		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20543

AN:

151936

Hom.:

2807

Cov.:

show subpopulations

Gnomad AFR

AF:

0.181

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.726

Gnomad SAS

AF:

0.255

Gnomad FIN

AF:

0.0734

Gnomad MID

AF:

0.0513

Gnomad NFE

AF:

0.0521

Gnomad OTH

AF:

0.132

GnomAD2 exomes

AF:

0.175

AC:

44067

AN:

251142

AF XY:

0.166

show subpopulations

Gnomad AFR exome

AF:

0.180

Gnomad AMR exome

AF:

0.338

Gnomad ASJ exome

AF:

0.0457

Gnomad EAS exome

AF:

0.732

Gnomad FIN exome

AF:

0.0691

Gnomad NFE exome

AF:

0.0524

Gnomad OTH exome

AF:

0.128

GnomAD4 exome

AF:

0.0969

AC:

141638

AN:

1461644

Hom.:

20282

Cov.:

AF XY:

0.0991

AC XY:

72070

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.185

AC:

6182

AN:

33476

American (AMR)

AF:

0.319

AC:

14249

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

1160

AN:

26132

East Asian (EAS)

AF:

0.778

AC:

30880

AN:

39698

South Asian (SAS)

AF:

0.236

AC:

20315

AN:

86252

European-Finnish (FIN)

AF:

0.0707

AC:

3775

AN:

53384

Middle Eastern (MID)

AF:

0.0571

AC:

329

AN:

5766

European-Non Finnish (NFE)

AF:

0.0518

AC:

57571

AN:

1111840

Other (OTH)

AF:

0.119

AC:

7177

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

6591

13182

19774

26365

32956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2756

5512

8268

11024

13780

<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:

0.135

AC:

20568

AN:

152054

Hom.:

2810

Cov.:

AF XY:

0.142

AC XY:

10575

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.181

AC:

7488

AN:

41474

American (AMR)

AF:

0.210

AC:

3208

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

169

AN:

3470

East Asian (EAS)

AF:

0.727

AC:

3748

AN:

5154

South Asian (SAS)

AF:

0.255

AC:

1231

AN:

4828

European-Finnish (FIN)

AF:

0.0734

AC:

777

AN:

10582

Middle Eastern (MID)

AF:

0.0517

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0521

AC:

3545

AN:

67990

Other (OTH)

AF:

0.136

AC:

287

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

768

1536

2304

3072

3840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.0809

Hom.:

1508

Bravo

AF:

0.152

Asia WGS

AF:

0.439

AC:

1524

AN:

3478

EpiCase

AF:

0.0492

EpiControl

AF:

0.0496

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jun 23, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2014

Eurofins Ntd Llc (ga)

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

- -

Autosomal recessive nonsyndromic hearing loss 23

Benign:1

Sep 05, 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

-0.85

CADD

Benign

2.8

(source)

DANN

Benign

0.41

PhyloP100

-0.46

Mutation Taster

=100/0

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