rs201534861

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_033056.4(PCDH15):c.4463A>G(p.Asn1488Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N1488N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.40

Publications

1 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012073994).

BP6

Variant 10-53823263-T-C is Benign according to our data. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53823263-T-C is described in CliVar as Likely_benign. Clinvar id is 227840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.4463A>G	p.Asn1488Ser	missense_variant	Exon 33 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.4368-3033A>G		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.4463A>G	p.Asn1488Ser	missense_variant	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.4368-3033A>G		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000916

AC:

AN:

251204

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.000806

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111936

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000772

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 17, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn1488Ser in exon 33 of PCDH15: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, over 10 mammals have a serine (Ser) at this position. Additional computa tional prediction tools do not suggest a high likelihood of impact to the protei n. This variant has been identified in 0.14% (12/8654) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs201534861). -

Inborn genetic diseases

Benign:1

Jun 30, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.0053

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.011

MetaRNN

Benign

0.012

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

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.41

.;.;.;.;.;.;.;.;N

PhyloP100

1.4

PrimateAI

Benign

0.21

PROVEAN

Benign

0.16

N;.;.;N;N;N;.;N;N

REVEL

Benign

0.086

Sift

Benign

0.56

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

Sift4G

Benign

0.30

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

Polyphen

0.0010

B;.;.;B;B;B;.;B;B

Vest4

0.061

MutPred

0.25

.;.;.;Gain of glycosylation at N1490 (P = 0.0308);.;.;.;.;.;

MVP

0.39

MPC

0.025

ClinPred

0.016

GERP RS

-1.6

Varity_R

0.029

gMVP

0.14

Mutation Taster

=92/8

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

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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