rs45483395

Positions:

• chr10-53961876-C-A
• chr10-53961876-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_033056.4(PCDH15):​c.2885G>T​(p.Arg962Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,608,790 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. R962C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: PCDH15 NM_033056.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 1.20

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 Benign. Variant got -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-53961877-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.009616345).
• BP6: Variant 10-53961876-C-A is Benign according to our data. Variant chr10-53961876-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46458.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr10-53961876-C-A is described in Lovd as [Benign]. Variant chr10-53961876-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00304 (462/152180) while in subpopulation AMR AF= 0.00851 (130/15278). AF 95% confidence interval is 0.00732. There are 2 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.2885G>T	p.Arg962Leu	missense_variant	22/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.2885G>T	p.Arg962Leu	missense_variant	22/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.2885G>T	p.Arg962Leu	missense_variant	22/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.2885G>T	p.Arg962Leu	missense_variant	22/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 462 AN: 152062 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00859

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00267 AC: 671 AN: 250940 Hom.: 1 AF XY: 0.00273 AC XY: 370 AN XY: 135628

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00498

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00300 AC: 4377 AN: 1456610 Hom.: 9 Cov.: 29 AF XY: 0.00299 AC XY: 2165 AN XY: 724762

Gnomad4 AFR exome AF: 0.000840

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00193

Gnomad4 NFE exome AF: 0.00347

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00304 AC: 462 AN: 152180 Hom.: 2 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74404

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00340

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00376 Hom.: 2

Bravo AF: 0.00304

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00311 AC: 12

ExAC AF: 0.00208 AC: 253

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PCDH15: PM5, BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 11, 2013	p.Arg962Leu in exon 22 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.3% (35/11558) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45483395). In addition, a different variant at the same position (p.Arg 962His) has also been identified in 0.7% (73/10320) of African chromosomes (ExAC , http://exac.broadinstitute.org; dbSNP rs45483395). The arginine (Arg) at posit ion 962 is not conserved in mammals or evolutionarily distant species and 5 spec ies (Zebra finch, and 4 fish) carry a leucine (Leu) at this position, raising th e possibility that this change may be tolerated. Additional computational predic tion tools suggest that this variant may not impact the protein. -

Usher syndrome type 1F Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Usher syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

PCDH15-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.59	D
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
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0096	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.58	.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N
MutationTaster	Benign	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	.;.;.;.;.;.;.;N;.;N;N;.;N;.;.;N;N;N;.;N;N
REVEL	Benign	0.13
Sift	Benign	0.16	.;.;.;.;.;.;.;T;.;T;T;.;T;.;.;T;T;T;.;T;T
Sift4G	Benign	0.23	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.013, 0.023, 0.97, 0.10, 0.039	.;.;.;.;.;.;.;.;.;.;B;.;B;.;.;B;D;D;.;B;B
Vest4		0.32
MVP		0.62
MPC		0.032
ClinPred		0.022	T
GERP RS		1.7
Varity_R		0.25
gMVP		0.52

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: rs45483395; hg19: chr10-55721636;