rs1248401224

chr10-53866639-T-TA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_033056.4(PCDH15):c.3717+2_3717+3insT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,196 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PCDH15 NM_033056.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.32

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-53866639-T-TA is Pathogenic according to our data. Variant chr10-53866639-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553548.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.3717+2_3717+3insT		splice_region_variant, intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.3717+2_3717+3insT		splice_region_variant, intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.3717+2_3717+3insT		splice_region_variant, intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.3717+2_3717+3insT		splice_region_variant, intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250884 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

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: 0.00000205 AC: 3 AN: 1460196 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726520

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 1F Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 21, 2022	Variant summary: PCDH15 c.3717+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, significantly altering the expected protein size. (Aparisi_2013). The variant allele was found at a frequency of 1.2e-05 in 250884 control chromosomes. c.3717+2dupT has been reported in the literature in individuals affected with Usher Syndrome Type 1F (e.g. Jaijo_2012, Aparisi_2014). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, with one lab citing the variant as pathogenic, one as likely pathogenic, and one as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The c.3717+2dup variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 22815625, 23451239, 25404053) and has been identified in 0.009% (3/34464) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1248401224). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 553548) and has been interpreted as pathogenic or likely pathogenic by Invitae and Natera, Inc., and as a variant of uncertain significance by Counsyl. Of the 2 affected individuals, 1 of those was a homozygote and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the c.3717+2dup variant is pathogenic (PMID: 22815625, 23451239, 25404053). In vitro functional studies provide some evidence that the c.3717+2dup variant may impact protein function (PMID: 23451239). However, these types of assays may not accurately represent biological function. This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PM2_supporting, PP3, PM3, PS3_moderate (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 29, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 30, 2020	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2023	Published functional studies suggest the c.3717+2dupT results in the skipping of exon 27 and utilization of a cryptic splice site (Aparisi et al., 2013); Intronic splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25404053, 22815625, 23451239) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 27, but is expected to preserve the integrity of the reading-frame (PMID: 23451239). ClinVar contains an entry for this variant (Variation ID: 553548). This variant is also known as c.3717+2dupTT. This variant has been observed in individual(s) with Usher syndrome (PMID: 22815625, 25404053). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change falls in intron 27 of the PCDH15 gene. It does not directly change the encoded amino acid sequence of the PCDH15 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.63		Position offset: -48
DS_DL_spliceai		0.93		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1248401224; hg19: chr10-55626399;