rs41307518

chr10-53959836-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_033056.4(PCDH15):c.3018G>T(p.Val1006=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,068 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1006V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (24 hom.)
• Consequence: PCDH15 NM_033056.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0270

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-53959836-C-A is Benign according to our data. Variant chr10-53959836-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 46461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53959836-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.027 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00198 (301/152204) while in subpopulation SAS AF= 0.0172 (83/4826). AF 95% confidence interval is 0.0142. There are 2 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.3018G>T	p.Val1006=	synonymous_variant	23/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.3018G>T	p.Val1006=	synonymous_variant	23/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.3018G>T	p.Val1006=	synonymous_variant	23/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.3018G>T	p.Val1006=	synonymous_variant	23/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152086 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00343 AC: 861 AN: 251356 Hom.: 9 AF XY: 0.00424 AC XY: 576 AN XY: 135850

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0159

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00242

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00335 AC: 4889 AN: 1460864 Hom.: 24 Cov.: 30 AF XY: 0.00375 AC XY: 2725 AN XY: 726784

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00277

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152204 Hom.: 2 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74420

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00211 Hom.: 1

Bravo AF: 0.00155

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 26, 2010	Val1006Val in exon 23 of PCDH15: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located near a splice junction and is presnet in dbSNP (rs41307518 - 5 submissions). -

Usher syndrome type 1F Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2019	This variant is associated with the following publications: (PMID: 16679490) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Usher syndrome type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	2.0
Dann	Benign	0.65

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: rs41307518; hg19: chr10-55719596;