rs140516168

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001384140.1(PCDH15):c.1606G>C(p.Ala536Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,630 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PCDH15
NM_001384140.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.60

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21211696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.1606G>C	p.Ala536Pro	missense_variant	14/33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.1606G>C	p.Ala536Pro	missense_variant	14/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.1606G>C	p.Ala536Pro	missense_variant	14/33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.1606G>C	p.Ala536Pro	missense_variant	14/38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000478

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251040

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000151

AC:

AN:

1461568

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000171

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.000604

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 07, 2022	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 536 of the PCDH15 protein (p.Ala536Pro). This variant is present in population databases (rs140516168, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 229135). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2017	The p.Ala536Pro variant (rs140516168) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.05 percent in the African population (identified on 13 out of 24,018 chromosomes) and has been reported to the ClinVar database as a variant of unknown significance (Variation ID: 229135). The alanine at position 536 is moderately conserved considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Ala536Pro variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Ala536Pro variant with certainty. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 06, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Ala536Pro var iant in PCDH15 has not been previously reported in individuals with hearing loss , but has been identified in 0.1% (11/10404) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140516168 ). The alanine (Ala) at position 536 is not conserved through species, with 2 ma mmals (dolphin and killer whale) having a proline (Pro) at this position, sugges ting that changes at this position may be tolerated. Additional computational pr ediction tools do not provide strong support for or against an impact to the pro tein. In summary, while the clinical significance of the p.Ala536Pro variant is uncertain, the conservation data suggest that it is more likely to be benign. -

Usher syndrome type 1F

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 21, 2020

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The c.1606G>C (p.A536P) alteration is located in exon 14 (coding exon 13) of the PCDH15 gene. This alteration results from a G to C substitution at nucleotide position 1606, causing the alanine (A) at amino acid position 536 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

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

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;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

0.081

MetaRNN

Benign

0.21

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

-0.56

MutationAssessor

Benign

0.80

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

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.6

.;.;.;.;.;.;.;D;N;.;N;N;.;N;.;.;N;N;N;.;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.21

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

Sift4G

Uncertain

0.013

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

Polyphen

1.0, 0.95, 0.79, 1.0, 1.0

.;.;.;.;.;.;.;.;.;.;.;D;.;P;.;.;P;D;D;.;D;D;D

Vest4

0.47

MVP

0.77

MPC

0.038

ClinPred

0.19

GERP RS

4.4

Varity_R

0.63

gMVP

0.64

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over