rs111033516

chr10-54020318-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_033056.4(PCDH15):c.2625G>A(p.Ser875=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00553 in 1,613,736 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S875S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (36 hom.)
• Consequence: PCDH15 NM_033056.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -1.33

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-54020318-C-T is Benign according to our data. Variant chr10-54020318-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46454.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=1}. Variant chr10-54020318-C-T is described in Lovd as [Benign]. Variant chr10-54020318-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00387 (588/152092) while in subpopulation NFE AF= 0.00631 (429/67948). AF 95% confidence interval is 0.00582. There are 6 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.2625G>A	p.Ser875=	synonymous_variant	20/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.2625G>A	p.Ser875=	synonymous_variant	20/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.2625G>A	p.Ser875=	synonymous_variant	20/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.2625G>A	p.Ser875=	synonymous_variant	20/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 589 AN: 151974 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00440

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00633

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00345 AC: 866 AN: 251258 Hom.: 2 AF XY: 0.00337 AC XY: 457 AN XY: 135788

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00584

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00571 AC: 8344 AN: 1461644 Hom.: 36 Cov.: 32 AF XY: 0.00549 AC XY: 3993 AN XY: 727122

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00232

Gnomad4 NFE exome AF: 0.00696

Gnomad4 OTH exome AF: 0.00460

GnomAD4 genome AF: 0.00387 AC: 588 AN: 152092 Hom.: 6 Cov.: 32 AF XY: 0.00358 AC XY: 266 AN XY: 74314

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00440

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00631

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00469 Hom.: 2

Bravo AF: 0.00377

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00535

EpiControl AF: 0.00616

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 15, 2012	Ser875Ser in exon 20 of PCDH15: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, has been identified in 0.5% (38/7020) of Europe an American chromosomes and 0.1% (5/3736) of African American chromosomes from a broad population by the NHLBI Exome sequencing project (http://evs.gs.washingto n.edu/EVS/; dbSNP rs111033516). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2016	- -

Usher syndrome type 1F Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PCDH15: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	7.6
Dann	Benign	0.58

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: rs111033516; hg19: chr10-55780078;