rs41274634

Positions:

• chr10-54236848-T-C

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.960A>G​(p.Pro320=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,613,256 control chromosomes in the GnomAD database, including 951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (62 hom., cov: 32)
  • Exomes 𝑓: 0.030 (889 hom.)
• Consequence: PCDH15 NM_033056.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.818

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=-0.63).
• BP6: Variant 10-54236848-T-C is Benign according to our data. Variant chr10-54236848-T-C is described in ClinVar as [Benign]. Clinvar id is 46513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54236848-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.818 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.960A>G	p.Pro320=	synonymous_variant	9/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.960A>G	p.Pro320=	synonymous_variant	9/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.960A>G	p.Pro320=	synonymous_variant	9/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.960A>G	p.Pro320=	synonymous_variant	9/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3851 AN: 152138 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0784

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0301 AC: 7560 AN: 251394 Hom.: 180 AF XY: 0.0326 AC XY: 4431 AN XY: 135864

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.0394

Gnomad ASJ exome AF: 0.00962

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.0777

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0297 AC: 43321 AN: 1461000 Hom.: 889 Cov.: 31 AF XY: 0.0311 AC XY: 22580 AN XY: 726864

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.0353

Gnomad4 ASJ exome AF: 0.00957

Gnomad4 EAS exome AF: 0.00129

Gnomad4 SAS exome AF: 0.0809

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0267

GnomAD4 genome AF: 0.0253 AC: 3859 AN: 152256 Hom.: 62 Cov.: 32 AF XY: 0.0263 AC XY: 1959 AN XY: 74430

Gnomad4 AFR AF: 0.0216

Gnomad4 AMR AF: 0.0343

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0780

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0263

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0259 Hom.: 34

Bravo AF: 0.0240

Asia WGS AF: 0.0400 AC: 141 AN: 3478

EpiCase AF: 0.0244

EpiControl AF: 0.0207

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 20, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 14, 2010	Pro320Pro in exon 9 of PCDH15: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located near a splice junction and is listed in dbSNP (rs41274634 - no frequency data availabl e). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2013	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. -

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	-0.63
CADD	Benign	4.2
DANN	Benign	0.62

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: rs41274634; hg19: chr10-55996608;