10-53866865-G-A

Position:

• chr10-53866865-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000320301.11(PCDH15):​c.3502-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 1,557,730 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0054 (34 hom.)
• Consequence: PCDH15 ENST00000320301.11 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003810
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -0.109

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-53866865-G-A is Benign according to our data. Variant chr10-53866865-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46469.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=1, Uncertain_significance=1}. Variant chr10-53866865-G-A is described in Lovd as [Benign]. Variant chr10-53866865-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00407 (558/136958) while in subpopulation NFE AF= 0.00538 (355/65964). AF 95% confidence interval is 0.00492. There are 1 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.3502-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644397.2	NP_001371069.1
PCDH15	NM_033056.4	c.3502-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320301.11	NP_149045.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3502-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.3502-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.00408 AC: 558 AN: 136852 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00525

Gnomad ASJ AF: 0.00859

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00164

Gnomad MID AF: 0.0129

Gnomad NFE AF: 0.00538

Gnomad OTH AF: 0.0111

GnomAD3 exomes AF: 0.00443 AC: 1069 AN: 241144 Hom.: 4 AF XY: 0.00432 AC XY: 566 AN XY: 130922

Gnomad AFR exome AF: 0.000771

Gnomad AMR exome AF: 0.00507

Gnomad ASJ exome AF: 0.00819

Gnomad EAS exome AF: 0.0000649

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00175

Gnomad NFE exome AF: 0.00614

Gnomad OTH exome AF: 0.00765

GnomAD4 exome AF: 0.00544 AC: 7734 AN: 1420772 Hom.: 34 Cov.: 26 AF XY: 0.00532 AC XY: 3774 AN XY: 709346

Gnomad4 AFR exome AF: 0.00133

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.00729

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.00222

Gnomad4 NFE exome AF: 0.00610

Gnomad4 OTH exome AF: 0.00648

GnomAD4 genome AF: 0.00407 AC: 558 AN: 136958 Hom.: 1 Cov.: 31 AF XY: 0.00365 AC XY: 242 AN XY: 66348

Gnomad4 AFR AF: 0.00162

Gnomad4 AMR AF: 0.00524

Gnomad4 ASJ AF: 0.00859

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00164

Gnomad4 NFE AF: 0.00538

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00447 Hom.: 1

Bravo AF: 0.00447

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2019	- -
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	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PCDH15: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	3502-8C>T in Intron 26 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.7% (52/7020) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2018	Variant summary: The PCDH15 c.3502-8C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1152/262912 control chromosomes (6 homozygotes), predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.008337 (83/9956). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic PCDH15 variant (0.0031623), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. The variant of interest has been reported in a study cohort of UK Usher patients, and was classified by authors as neutral (Le Quesne Stabej_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 02, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Usher syndrome type 1 Uncertain:1

Uncertain significance, 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, 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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2020

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

Usher syndrome type 1F Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 21, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.21
DANN	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0
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: rs184144118; hg19: chr10-55626625;