10-54195684-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_033056.4(PCDH15):c.1304A>C(p.Asp435Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,610,574 control chromosomes in the GnomAD database, including 39,899 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 3801 hom., cov: 32)

Exomes 𝑓: 0.18 ( 36098 hom. )

Consequence

PCDH15
NM_033056.4 missense, splice_region

Scores

Splicing: ADA: 0.9938

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 7.99

Publications

55 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 -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 10-54195684-T-G is Benign according to our data. Variant chr10-54195684-T-G is described in ClinVar as Benign. ClinVar VariationId is 46440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.1304A>C	p.Asp435Ala	missense_variant, splice_region_variant	Exon 11 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.1304A>C	p.Asp435Ala	missense_variant, splice_region_variant	Exon 11 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.1304A>C	p.Asp435Ala	missense_variant, splice_region_variant	Exon 11 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.1304A>C	p.Asp435Ala	missense_variant, splice_region_variant	Exon 11 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26747

AN:

152036

Hom.:

3799

Cov.:

show subpopulations

Gnomad AFR

AF:

0.131

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.212

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.843

Gnomad SAS

AF:

0.370

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.139

Gnomad OTH

AF:

0.176

GnomAD2 exomes

AF:

0.240

AC:

60262

AN:

251270

AF XY:

0.240

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.843

Gnomad FIN exome

AF:

0.144

Gnomad NFE exome

AF:

0.143

Gnomad OTH exome

AF:

0.208

GnomAD4 exome

AF:

0.178

AC:

258923

AN:

1458420

Hom.:

36098

Cov.:

AF XY:

0.182

AC XY:

132192

AN XY:

725766

show subpopulations

African (AFR)

AF:

0.130

AC:

4318

AN:

33304

American (AMR)

AF:

0.280

AC:

12515

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

3628

AN:

26116

East Asian (EAS)

AF:

0.870

AC:

34508

AN:

39660

South Asian (SAS)

AF:

0.341

AC:

29344

AN:

86152

European-Finnish (FIN)

AF:

0.146

AC:

7789

AN:

53404

Middle Eastern (MID)

AF:

0.202

AC:

1162

AN:

5758

European-Non Finnish (NFE)

AF:

0.138

AC:

153501

AN:

1109056

Other (OTH)

AF:

0.202

AC:

12158

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

8949

17898

26847

35796

44745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5948

11896

17844

23792

29740

<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:

0.176

AC:

26758

AN:

152154

Hom.:

3801

Cov.:

AF XY:

0.186

AC XY:

13838

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.131

AC:

5424

AN:

41524

American (AMR)

AF:

0.213

AC:

3248

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

470

AN:

3472

East Asian (EAS)

AF:

0.843

AC:

4337

AN:

5142

South Asian (SAS)

AF:

0.369

AC:

1782

AN:

4826

European-Finnish (FIN)

AF:

0.143

AC:

1514

AN:

10590

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.139

AC:

9432

AN:

67998

Other (OTH)

AF:

0.180

AC:

381

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

994

1987

2981

3974

4968

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

282

564

846

1128

1410

<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:

0.165

Hom.:

14052

Bravo

AF:

0.182

TwinsUK

AF:

0.129

AC:

478

ALSPAC

AF:

0.143

AC:

551

ESP6500AA

AF:

0.131

AC:

579

ESP6500EA

AF:

0.132

AC:

1133

ExAC

AF:

0.238

AC:

28895

Asia WGS

AF:

0.575

AC:

1995

AN:

3478

EpiCase

AF:

0.146

EpiControl

AF:

0.145

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19816713, 27275418, 22815625) -

not specified

Benign:3

Jun 21, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1F

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

T;.;.;.;.;T;.;T;.;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;T;D;D;T;T;T;D;T;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0000011

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;.;.;.;L;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;L;L

PhyloP100

8.0

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.2

D;.;.;D;.;.;N;.;D;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0090

D;.;.;D;.;.;D;.;T;D;.;D;D;.;T;.;.;D;D;D;.;T;D;D

Sift4G

Uncertain

0.0090

D;.;D;D;D;D;T;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.87, 0.97, 0.88, 0.99, 0.99, 0.95, 0.84

.;.;.;.;.;.;.;.;.;.;.;.;P;.;D;.;.;P;D;D;.;D;P;P

Vest4

0.53

MPC

0.13

ClinPred

0.020

GERP RS

5.1

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.23

gMVP

0.41

Mutation Taster

=55/45

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.95

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