rs199469706

chr10-54213945-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033056.4(PCDH15):c.1088del(p.Leu363TrpfsTer58) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000014 in 1,429,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L363L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCDH15 NM_033056.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.66

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-54213945-CA-C is Pathogenic according to our data. Variant chr10-54213945-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 4932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54213945-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.1088del	p.Leu363TrpfsTer58	frameshift_variant	10/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.1088del	p.Leu363TrpfsTer58	frameshift_variant	10/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.1088del	p.Leu363TrpfsTer58	frameshift_variant	10/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.1088del	p.Leu363TrpfsTer58	frameshift_variant	10/38		NM_001384140.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1429026 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 712784

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 02, 2023

- -

Usher syndrome type 1F Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 05, 2012

- -

Usher syndrome type 1D Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 27, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 14, 2022

This sequence change creates a premature translational stop signal (p.Leu363Trpfs*58) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 11487575). ClinVar contains an entry for this variant (Variation ID: 4932). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199469706; hg19: chr10-55973705;