rs7089209

Positions:

• chr10-53831553-G-A
• chr10-53831553-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033056.4(PCDH15):​c.3984-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,521,810 control chromosomes in the GnomAD database, including 134,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11786 hom., cov: 33)
  • Exomes 𝑓: 0.42 (122971 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0570

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-53831553-G-A is Benign according to our data. Variant chr10-53831553-G-A is described in ClinVar as [Benign]. Clinvar id is 46476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53831553-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.3984-20C>T		intron_variant		ENST00000644397.2	NP_001371069.1
PCDH15	NM_033056.4	c.3984-20C>T		intron_variant		ENST00000320301.11	NP_149045.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.3984-20C>T		intron_variant		1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.3984-20C>T		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58115 AN: 151836 Hom.: 11788 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.375

GnomAD3 exomes AF: 0.430 AC: 105821 AN: 246134 Hom.: 24135 AF XY: 0.427 AC XY: 57079 AN XY: 133598

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.478

Gnomad ASJ exome AF: 0.340

Gnomad EAS exome AF: 0.750

Gnomad SAS exome AF: 0.469

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.393

GnomAD4 exome AF: 0.417 AC: 570689 AN: 1369856 Hom.: 122971 Cov.: 21 AF XY: 0.417 AC XY: 286528 AN XY: 686630

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.467

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.790

Gnomad4 SAS exome AF: 0.471

Gnomad4 FIN exome AF: 0.386

Gnomad4 NFE exome AF: 0.404

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.383 AC: 58131 AN: 151954 Hom.: 11786 Cov.: 33 AF XY: 0.384 AC XY: 28486 AN XY: 74272

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.407

Gnomad4 ASJ AF: 0.346

Gnomad4 EAS AF: 0.748

Gnomad4 SAS AF: 0.481

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.397

Gnomad4 OTH AF: 0.377

Alfa AF: 0.378 Hom.: 2403

Bravo AF: 0.381

Asia WGS AF: 0.566 AC: 1966 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2010	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 1F Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.45

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: rs7089209; hg19: chr10-55591313; COSMIC: COSV57367938;