rs373916538

chr10-53822439-CAGGAGCAGG-Cchr10-53822439-CAGGAGCAGG-CAGGAGCAGGAGGAGCAGG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_033056.4(PCDH15):c.5278_5286del(p.Pro1760_Pro1762del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,587,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1760P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PCDH15 NM_033056.4 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.46

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-53822439-CAGGAGCAGG-C is Benign according to our data. Variant chr10-53822439-CAGGAGCAGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 421481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53822439-CAGGAGCAGG-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.5278_5286del	p.Pro1760_Pro1762del	inframe_deletion	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-2218_4368-2210del		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.5278_5286del	p.Pro1760_Pro1762del	inframe_deletion	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-2218_4368-2210del		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 171 AN: 149610 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00407

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000313 AC: 66 AN: 211150 Hom.: 0 AF XY: 0.000244 AC XY: 28 AN XY: 114690

Gnomad AFR exome AF: 0.00440

Gnomad AMR exome AF: 0.000160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000658

Gnomad SAS exome AF: 0.0000358

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000335

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.000124 AC: 178 AN: 1437614 Hom.: 0 AF XY: 0.000130 AC XY: 93 AN XY: 713570

Gnomad4 AFR exome AF: 0.00336

Gnomad4 AMR exome AF: 0.000215

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.000107

Gnomad4 SAS exome AF: 0.0000477

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000273

Gnomad4 OTH exome AF: 0.000303

GnomAD4 genome AF: 0.00114 AC: 171 AN: 149726 Hom.: 0 Cov.: 32 AF XY: 0.00119 AC XY: 87 AN XY: 73102

Gnomad4 AFR AF: 0.00406

Gnomad4 AMR AF: 0.000400

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000569 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PCDH15: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2020	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2017	p.Pro1760_Pro1762del in exon 33 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.4% (77/20736) of Afric an chromosomes by the Genome Aggregation Database (gnomAD, http://exac.broadinst itute.org; dbSNP rs373916538). -

PCDH15-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2023

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373916538; hg19: chr10-55582199;