rs1554820012

Positions:

• chr10-53822383-GGGAGGAGGACAAAAAAGAGAAAAAGGAGAAATGTCAGGAGGAGGAGCAAGAGGAGCAGGAGCA-G

Variant summary

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

The ENST00000320301.11(PCDH15):​c.5280_5342del​(p.Ala1761_Pro1781del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,572,742 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 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: PCDH15 ENST00000320301.11 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.97

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 10-53822383-GGGAGGAGGACAAAAAAGAGAAAAAGGAGAAATGTCAGGAGGAGGAGCAAGAGGAGCAGGAGCA-G is Benign according to our data. Variant chr10-53822383-GGGAGGAGGACAAAAAAGAGAAAAAGGAGAAATGTCAGGAGGAGGAGCAAGAGGAGCAGGAGCA-G is described in ClinVar as [Likely_benign]. Clinvar id is 179750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.5280_5342del	p.Ala1761_Pro1781del	inframe_deletion	33/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4368-2216_4368-2154del		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.5280_5342del	p.Ala1761_Pro1781del	inframe_deletion	33/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.4368-2216_4368-2154del		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 183 AN: 151128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000319 AC: 58 AN: 182056 Hom.: 0 AF XY: 0.000225 AC XY: 22 AN XY: 97826

Gnomad AFR exome AF: 0.00520

Gnomad AMR exome AF: 0.0000371

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000992 AC: 141 AN: 1421496 Hom.: 0 AF XY: 0.0000895 AC XY: 63 AN XY: 703916

Gnomad4 AFR exome AF: 0.00371

Gnomad4 AMR exome AF: 0.000184

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000275

Gnomad4 OTH exome AF: 0.000170

GnomAD4 genome AF: 0.00121 AC: 183 AN: 151246 Hom.: 0 Cov.: 32 AF XY: 0.00104 AC XY: 77 AN XY: 73868

Gnomad4 AFR AF: 0.00437

Gnomad4 AMR AF: 0.0000662

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000334 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 28, 2014

Ala1761_Pro1781del in exon 33 of PCDH15: This variant is not expected to have cl inical significance because it has been identified in 0.8% (66/8214) of European American chromosomes and in 0.9% (39/4326) of African American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). In addit ion, the exon 33 region of PCDH15 is not conserved across species. -

PCDH15-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 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, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 22, 2021

- -

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: rs1554820012; hg19: chr10-55582143;