rs7921598

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.1263T>C(p.Thr421Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,613,080 control chromosomes in the GnomAD database, including 23,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 6057 hom., cov: 32)

Exomes 𝑓: 0.14 ( 17371 hom. )

Consequence

PCDH15
NM_033056.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.223

Publications

19 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=-0.81).

BP6

Variant 10-54195725-A-G is Benign according to our data. Variant chr10-54195725-A-G is described in ClinVar as Benign. ClinVar VariationId is 46439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.223 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.1263T>C	p.Thr421Thr	synonymous_variant	Exon 11 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 link	c.1263T>C	p.Thr421Thr	synonymous_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.1263T>C	p.Thr421Thr	synonymous_variant	Exon 11 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2 link	c.1263T>C	p.Thr421Thr	synonymous_variant	Exon 11 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

35002

AN:

151942

Hom.:

6041

Cov.:

show subpopulations

Gnomad AFR

AF:

0.489

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.0910

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.208

GnomAD2 exomes

AF:

0.165

AC:

41539

AN:

251378

AF XY:

0.158

show subpopulations

Gnomad AFR exome

AF:

0.496

Gnomad AMR exome

AF:

0.211

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.0950

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.157

GnomAD4 exome

AF:

0.140

AC:

203946

AN:

1461022

Hom.:

17371

Cov.:

AF XY:

0.139

AC XY:

100829

AN XY:

726858

show subpopulations

African (AFR)

AF:

0.504

AC:

16856

AN:

33440

American (AMR)

AF:

0.212

AC:

9470

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

3112

AN:

26122

East Asian (EAS)

AF:

0.0669

AC:

2655

AN:

39670

South Asian (SAS)

AF:

0.179

AC:

15448

AN:

86230

European-Finnish (FIN)

AF:

0.113

AC:

6014

AN:

53418

Middle Eastern (MID)

AF:

0.174

AC:

1002

AN:

5760

European-Non Finnish (NFE)

AF:

0.126

AC:

139956

AN:

1111292

Other (OTH)

AF:

0.156

AC:

9433

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

8194

16387

24581

32774

40968

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5364

10728

16092

21456

26820

<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:

0.231

AC:

35063

AN:

152058

Hom.:

6057

Cov.:

AF XY:

0.226

AC XY:

16830

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.488

AC:

20230

AN:

41416

American (AMR)

AF:

0.199

AC:

3047

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

410

AN:

3472

East Asian (EAS)

AF:

0.0910

AC:

470

AN:

5166

South Asian (SAS)

AF:

0.181

AC:

870

AN:

4818

European-Finnish (FIN)

AF:

0.108

AC:

1146

AN:

10606

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8305

AN:

67992

Other (OTH)

AF:

0.211

AC:

445

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1148

2296

3444

4592

5740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.160

Hom.:

10427

Bravo

AF:

0.253

Asia WGS

AF:

0.163

AC:

569

AN:

3478

EpiCase

AF:

0.129

EpiControl

AF:

0.124

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1F

Benign:2

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

Benign:1

May 11, 2022

Fulgent Genetics, Fulgent Genetics

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

-0.81

CADD

Benign

7.9

(source)

DANN

Benign

0.36

PhyloP100

-0.22

PromoterAI

-0.025

Neutral

(source)

Mutation Taster

=98/2

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