rs111033496

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_033056.4(PCDH15):c.3795A>T(p.Glu1265Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,597,542 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 62 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 52 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0190

Publications

4 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 -16 ACMG points.

BP6

Variant 10-53857186-T-A is Benign according to our data. Variant chr10-53857186-T-A is described in ClinVar as Benign. ClinVar VariationId is 46474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2153/152150) while in subpopulation AFR AF = 0.0491 (2039/41504). AF 95% confidence interval is 0.0474. There are 62 homozygotes in GnomAd4. There are 1051 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 62 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.3795A>T	p.Glu1265Asp	missense_variant	Exon 28 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.3795A>T	p.Glu1265Asp	missense_variant	Exon 28 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.3795A>T	p.Glu1265Asp	missense_variant	Exon 28 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.3795A>T	p.Glu1265Asp	missense_variant	Exon 28 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2138

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00505

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.00367

AC:

921

AN:

250960

AF XY:

0.00274

show subpopulations

Gnomad AFR exome

AF:

0.0507

Gnomad AMR exome

AF:

0.00232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00141

AC:

2037

AN:

1445392

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

864

AN XY:

719950

show subpopulations

African (AFR)

AF:

0.0500

AC:

1651

AN:

33016

American (AMR)

AF:

0.00251

AC:

112

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39574

South Asian (SAS)

AF:

0.000187

AC:

AN:

85778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00507

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000474

AC:

AN:

1097544

Other (OTH)

AF:

0.00296

AC:

177

AN:

59820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

170

256

341

426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0142

AC:

2153

AN:

152150

Hom.:

Cov.:

AF XY:

0.0141

AC XY:

1051

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0491

AC:

2039

AN:

41504

American (AMR)

AF:

0.00505

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67996

Other (OTH)

AF:

0.0123

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

107

214

320

427

534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00260

Hom.:

Bravo

AF:

0.0161

ESP6500AA

AF:

0.0470

AC:

207

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00451

AC:

547

Asia WGS

AF:

0.00434

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 11, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 17, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Glu1265Asp in exon 28 of PCDH15: Glutamate at position 2072 is not conserved acr oss species (3 other amino acids at this position across 14 species) and the Asp artate variant is present in chicken and frog, suggesting that variation at this position is tolerated and unlikely to disrupt protein function. In addition, th is variant is predicted to be benign by three computational programs (AlignGVGD, SIFT, PolyPhen2). In summary, this variant is likely benign. -

not provided

Benign:2

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

- -

Usher syndrome type 1F

Benign:1

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

Benign

0.18

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0044

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

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0017

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

0.26

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

PhyloP100

0.019

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.34

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

REVEL

Benign

0.14

Sift

Benign

0.32

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

Sift4G

Benign

1.0

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

Polyphen

0.0010, 0.011, 0.0040, 0.0070

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

Vest4

0.15

MutPred

0.48

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;.;.;Gain of sheet (P = 0.039);.;.;.;Gain of sheet (P = 0.039);.;.;.;.;Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;.;.;Gain of sheet (P = 0.039);

MVP

0.60

MPC

0.027

ClinPred

0.0082

GERP RS

5.2

PromoterAI

-0.0080

Neutral

(source)

Varity_R

0.088

gMVP

0.39

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.40

Position offset: -11

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