rs749884609

Positions:

• chr10-53823312-CTGAGT-C
• chr10-53823312-CTGAGT-CTGAGTTGAGT

Variant summary

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

The ENST00000320301.11(PCDH15):​c.4409_4413del​(p.Asn1470SerfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N1470N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PCDH15 ENST00000320301.11 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.18

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 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 45 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-53823312-CTGAGT-C is Pathogenic according to our data. Variant chr10-53823312-CTGAGT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1068808.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.4409_4413del	p.Asn1470SerfsTer20	frameshift_variant	33/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4368-3087_4368-3083del		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.4409_4413del	p.Asn1470SerfsTer20	frameshift_variant	33/33	1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.4368-3087_4368-3083del		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251222 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461674 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727126

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	This sequence change creates a premature translational stop signal (p.Asn1470Serfs*20) in the PCDH15 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 486 amino acid(s) of the PCDH15 protein. This variant is present in population databases (rs749884609, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 1068808). This variant disrupts a region of the PCDH15 protein in which other variant(s) (p.Gln1576*) have been determined to be pathogenic (PMID: 28281779). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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: rs749884609; hg19: chr10-55583072;