rs58461416

chr10-53822440-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033056.4(PCDH15):c.5286T>A(p.Pro1762=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,592,162 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (90 hom.)
• Consequence: PCDH15 NM_033056.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.344

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-53822440-A-T is Benign according to our data. Variant chr10-53822440-A-T is described in ClinVar as [Benign]. Clinvar id is 46492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.344 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.5286T>A	p.Pro1762=	synonymous_variant	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-2210T>A		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.5286T>A	p.Pro1762=	synonymous_variant	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-2210T>A		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 450 AN: 150818 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.000666

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0747

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00655 AC: 1400 AN: 213664 Hom.: 60 AF XY: 0.00602 AC XY: 699 AN XY: 116058

Gnomad AFR exome AF: 0.000475

Gnomad AMR exome AF: 0.000221

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0878

Gnomad SAS exome AF: 0.000606

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.00437

GnomAD4 exome AF: 0.00199 AC: 2868 AN: 1441226 Hom.: 90 Cov.: 32 AF XY: 0.00187 AC XY: 1339 AN XY: 715488

Gnomad4 AFR exome AF: 0.000344

Gnomad4 AMR exome AF: 0.000213

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0639

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.0000690

Gnomad4 OTH exome AF: 0.00517

GnomAD4 genome AF: 0.00298 AC: 450 AN: 150936 Hom.: 20 Cov.: 32 AF XY: 0.00320 AC XY: 236 AN XY: 73808

Gnomad4 AFR AF: 0.000664

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0747

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000507 Hom.: 0

Bravo AF: 0.00365

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 25, 2010	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2017	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Usher syndrome type 1F Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Usher syndrome type 1 Benign:1

Benign, 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 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
BayesDel_noAF	Benign	-0.88
Cadd	Benign	7.6
Dann	Benign	0.41

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

Other links and lift over

dbSNP: rs58461416; hg19: chr10-55582200; COSMIC: COSV57405081; COSMIC: COSV57405081;