rs12359240

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000395445.6(PCDH15):c.4575C>T(p.Ile1525Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,613,842 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 38 hom. )

Consequence

PCDH15
ENST00000395445.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.363

Publications

3 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=-0.57).

BP6

Variant 10-53809469-G-A is Benign according to our data. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53809469-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 178516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.363 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00441 (671/152176) while in subpopulation NFE AF = 0.00541 (368/68000). AF 95% confidence interval is 0.00496. There are 4 homozygotes in GnomAd4. There are 298 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001384140.1 link	c.4671+1087C>T		intron_variant	Intron 37 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2 link	c.4671+1087C>T		intron_variant	Intron 37 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.00441

AC:

670

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00540

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00499

AC:

1240

AN:

248690

AF XY:

0.00511

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00377

Gnomad ASJ exome

AF:

0.0264

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00557

Gnomad OTH exome

AF:

0.00810

GnomAD4 exome

AF:

0.00556

AC:

8122

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00547

AC XY:

3974

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33480

American (AMR)

AF:

0.00411

AC:

184

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

746

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00386

AC:

333

AN:

86256

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.0236

AC:

136

AN:

5768

European-Non Finnish (NFE)

AF:

0.00546

AC:

6075

AN:

1111834

Other (OTH)

AF:

0.00846

AC:

511

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

497

994

1490

1987

2484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

238

476

714

952

1190

<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:

0.00441

AC:

671

AN:

152176

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

298

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41532

American (AMR)

AF:

0.00477

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0256

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00541

AC:

368

AN:

68000

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00581

Hom.:

Bravo

AF:

0.00517

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00676

EpiControl

AF:

0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCDH15: BP4, BP7, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 31, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ile1532Ile in Exon 37A of PCDH15: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 0.9% (50/5446) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12359240). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

0.36

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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