rs150509146

chr10-54185235-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033056.4(PCDH15):c.1339G>A(p.Asp447Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,613,308 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 2.48

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]

ACMG classification

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=0.13683957).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.1339G>A	p.Asp447Asn	missense_variant	12/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.1339G>A	p.Asp447Asn	missense_variant	12/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.1339G>A	p.Asp447Asn	missense_variant	12/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.1339G>A	p.Asp447Asn	missense_variant	12/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 151922 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

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: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251296 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135806

Gnomad AFR exome AF: 0.0000615

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: 0.000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000500 AC: 730 AN: 1461386 Hom.: 1 Cov.: 31 AF XY: 0.000488 AC XY: 355 AN XY: 727000

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

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: 0.000640

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000342 AC: 52 AN: 151922 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74204

Gnomad4 AFR AF: 0.000193

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: 0.000647

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 30, 2022	BP4, PM2_supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2022	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; This variant is associated with the following publications: (PMID: 15537665) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PCDH15: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 01, 2017	The p.Asp447Asn variant (rs150509146) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 46441). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.044% (identified in 56 out of 126,490 chromosomes). The aspartic acid at codon 447 is weakly conserved considering 12 species (Alamut software v2.9), and several species of fish have an asparagine at this position suggesting this change is evolutionary tolerated. Likewise, computational analyses suggest this variant does not have a significant effect on PCDH15 protein structure/function (SIFT: tolerated, PolyPhen2: benign). However, based on the available information, the clinical significance of the p.Asp447Asn variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 447 of the PCDH15 protein (p.Asp447Asn). This variant is present in population databases (rs150509146, gnomAD 0.04%). 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: 46441). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 11, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 11, 2014

The Asp447Asn variant in PCDH15 has been previously reported by our laboratory i n 1 individual with hearing loss and delayed walking, but a variant affecting th e remaining copy of PCDH15 was not identified. This variant has been identified in 0.06% (5/8600) of European American chromosomes by the NHLBI Exome Sequencin g Project and in 0.7% (1/1324) chromosomes by the ClinSeq project (http://evs.gs .washington.edu/EVS/; dbSNP rs150509146). Computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Asp447Asn variant is uncertain. -

Usher syndrome type 1F Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 17, 2020

- -

Usher syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.019	T;.;.;.;.;T;T;.;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Benign	0.045
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	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	0.030	D
MetaRNN	Benign	0.14	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	-0.67	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
REVEL	Benign	0.073
Sift4G	Benign	0.42	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.025, 0.18, 1.0, 0.39, 0.33, 0.0070	.;.;.;.;.;.;.;.;.;.;.;B;.;B;.;.;B;D;D;.;B;B;B
Vest4		0.21
MVP		0.71
MPC		0.030
ClinPred		0.090	T
GERP RS		5.3
Varity_R		0.28
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs150509146; hg19: chr10-55944995; COSMIC: COSV57363065;