rs748086016

Variant names:

• chr10-53822362-AAGAGGGATAGAAGGAGG-A
• rs748086016
• NM_033056.4:c.5347_5363delCCTCCTTCTATCCCTCT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_033056.4(PCDH15):​c.5347_5363delCCTCCTTCTATCCCTCT​(p.Pro1783SerfsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000937 in 1,578,922 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1783P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (1 hom.)
• Consequence: PCDH15 NM_033056.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:3
• Conservation: PhyloP100: 2.06
• Publications: 0 publications found

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]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.5347_5363delCCTCCTTCTATCCCTCT	p.Pro1783SerfsTer59	frameshift_variant	Exon 33 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4368-2149_4368-2133delCCTCCTTCTATCCCTCT		intron_variant	Intron 32 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.5347_5363delCCTCCTTCTATCCCTCT	p.Pro1783SerfsTer59	frameshift_variant	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.4368-2149_4368-2133delCCTCCTTCTATCCCTCT		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.0000594 AC: 9 AN: 151630 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

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: 0.0000884

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000105 AC: 20 AN: 189612 AF XY: 0.0000588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000389

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.0000974 AC: 139 AN: 1427292 Hom.: 1 AF XY: 0.0000947 AC XY: 67 AN XY: 707254

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32328

American (AMR) AF: 0.000622 AC: 24 AN: 38614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 37430

South Asian (SAS) AF: 0.00 AC: 0 AN: 83432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.0000988 AC: 108 AN: 1093236

Other (OTH) AF: 0.000118 AC: 7 AN: 59166

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000594 AC: 9 AN: 151630 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74050

African (AFR) AF: 0.00 AC: 0 AN: 41250

American (AMR) AF: 0.000198 AC: 3 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 1F Pathogenic:1 Uncertain:1 Benign:1

Mar 10, 2018

GeneID Lab - Advanced Molecular Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in an amino acid alteration replacing a proline (P) with a serine (S) at position 1783 creating a premature stop signal in the new reading frame noted as p.R80Pfs*69. The substitution is predicted to result in a non-functional PDCH15 protein, either through protein truncation or nonsense-mediated mRNA decay. This mutation is considered a non-tolerated amino acid change based on in silico prediction algorithms (disease causing), and it has not been reported in the ClinVar Database (NCBI National Library of Medicine, NIH, Bethesda MD), but it has been described in 12 alleles out of 50254, in the ExAC database, all of them belonging to heterozygous carries of Latino origin. Based on these findings and the limited literature regarding this substitution we consider it as a likely pathogenic variant. -

Aug 19, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 28, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:1 Uncertain:1 Benign:1

Aug 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 173 amino acids are replaced with 58 different amino acids, and other similar variants have been reported in HGMD; Has not been previously published as pathogenic or benign to our knowledge -

Nov 03, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PCDH15 c.5347_5363del17 (p.Pro1783SerfsX59) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00011 in 189612 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (0.00011 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5347_5363del17 in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. However, an upstream truncating variant NM_033056.4:c.4831_4834dup (p.Thr1612fs) has been universally classified as Likely Benign/Benign by at least 5 laboratories in ClinVar and has a gnomAD frequency of ~1% in the African/African American subpopulation, including 4 homozygotes. These data suggest the C-terminal region downstream of p.Thr1612 may be dispensable for PCDH15 function. ClinVar contains an entry for this variant (Variation ID: 555843). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=198/2	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs748086016; hg19: chr10-55582122;