NM_033056.4:c.2728G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_033056.4(PCDH15):c.2728G>T(p.Ala910Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,613,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A910T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 7.16

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041677326).

BP6

Variant 10-54020215-C-A is Benign according to our data. Variant chr10-54020215-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550483.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.2728G>T	p.Ala910Ser	missense_variant	Exon 20 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.2728G>T	p.Ala910Ser	missense_variant	Exon 20 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.2728G>T	p.Ala910Ser	missense_variant	Exon 20 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.2728G>T	p.Ala910Ser	missense_variant	Exon 20 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000918

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000917

AC:

AN:

250804

AF XY:

0.0000738

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461482

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33466

American (AMR)

AF:

0.000201

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111748

Other (OTH)

AF:

0.000132

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000283

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41538

American (AMR)

AF:

0.0000655

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67934

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000121

Hom.:

Bravo

AF:

0.000317

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCDH15: BS1:Supporting -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 27, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Ala910Ser var iant in PCDH15 has been reported in three individuals from Saudi Arabia with hea ring loss (Dallol 2016), and it has also been reported in ClinVar (Variation ID: 550483). This variant has also been identified in 0.12% (29/24020) African chro mosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction t ools and conservation analysis do not provide strong support for or against an i mpact to the protein. In summary, while the clinical significance of the p.Ala91 0Ser variant is uncertain, its frequency suggests that it is more likely to be b enign. ACMG/AMP Criteria applied: BS1_Supporting. -

PCDH15-related disorder

Uncertain:1

Jul 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PCDH15 c.2728G>T variant is predicted to result in the amino acid substitution p.Ala910Ser. This variant has been reported in three unrelated patients with hearing loss, although conclusive evidence of pathogenicity was not presented (described as p.Ala915Ser, Dallol et al. 2016. PubMed ID: 27766948). This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Usher syndrome type 1F

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Optic atrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Usher syndrome type 1D

Uncertain:1

Nov 08, 2021

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_033056.3(PCDH15):c.2728G>T(A910S) is a missense variant classified as a variant of uncertain significance in the context of PCDH15-related disorders. A910S has been observed in cases with relevant disease (PMID: 27766948). Functional assessments of this variant are not available in the literature. A910S has been observed in population frequency databases (gnomAD: AFR 0.11%). In summary, there is insufficient evidence to classify NM_033056.3(PCDH15):c.2728G>T(A910S) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

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

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.029

MetaRNN

Benign

0.042

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

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.33

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

PhyloP100

7.2

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.4

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

REVEL

Benign

0.28

Sift

Benign

0.066

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

Sift4G

Uncertain

0.0080

D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.99, 1.0, 0.99, 0.99

.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;D

Vest4

0.81

MVP

0.67

MPC

0.21

ClinPred

0.12

GERP RS

6.1

Varity_R

0.18

gMVP

0.64

Mutation Taster

=25/75

disease causing

(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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NM_033056.4:c.2728G>T

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