rs557936064

Positions:

• chr10-53822423-GGAGGAGCAA-G
• chr10-53822423-GGAGGAGCAA-GGAGGAGCAAGAGGAGCAA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_033056.4(PCDH15):​c.5294_5302del​(p.Leu1765_Pro1767del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,585,476 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: PCDH15 NM_033056.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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 Benign. Variant got -12 ACMG points.

• BP6: Variant 10-53822423-GGAGGAGCAA-G is Benign according to our data. Variant chr10-53822423-GGAGGAGCAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 167425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.5294_5302del	p.Leu1765_Pro1767del	inframe_deletion	33/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4368-2202_4368-2194del		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.5294_5302del	p.Leu1765_Pro1767del	inframe_deletion	33/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.4368-2202_4368-2194del		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 151416 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000562

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.000855

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00129 AC: 261 AN: 202002 Hom.: 0 AF XY: 0.00125 AC XY: 137 AN XY: 109406

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.00202 AC: 2901 AN: 1433942 Hom.: 2 AF XY: 0.00194 AC XY: 1378 AN XY: 711240

Gnomad4 AFR exome AF: 0.000312

Gnomad4 AMR exome AF: 0.000983

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000479

Gnomad4 FIN exome AF: 0.00209

Gnomad4 NFE exome AF: 0.00239

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.00125 AC: 190 AN: 151534 Hom.: 0 Cov.: 32 AF XY: 0.00115 AC XY: 85 AN XY: 74080

Gnomad4 AFR AF: 0.000560

Gnomad4 AMR AF: 0.000854

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	This variant is associated with the following publications: (PMID: 25307757) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PCDH15: BP3 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2015	p.Leu1765_Pro1767del in exon 33 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.4% (96/24474) of Europ ean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org). -

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2022

- -

PCDH15-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2021

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). -

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: rs557936064; hg19: chr10-55582183;