2-231737215-AC-A

Variant names:

• chr2-231737215-AC-A
• NM_002601.4:c.342delG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002601.4(PDE6D):​c.342delG​(p.Glu114AspfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE6D NM_002601.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.49

Genes affected

PDE6D (HGNC:8788): (phosphodiesterase 6D) This gene encodes the delta subunit of rod-specific photoreceptor phosphodiesterase (PDE), a key enzyme in the phototransduction cascade. A similar protein in cow functions in solubilizing membrane-bound PDE. In addition to its role in the PDE complex, the encoded protein is thought to bind to prenyl groups of proteins to target them to subcellular organelles called cilia. Mutations in this gene are associated with Joubert syndrome-22. Alternative splicing results in multiple splice variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.245 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-231737215-AC-A is Pathogenic according to our data. Variant chr2-231737215-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2001656.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6D	NM_002601.4	c.342delG	p.Glu114AspfsTer4	frameshift_variant	Exon 4 of 5	ENST00000287600.9	NP_002592.1
PDE6D	XM_047444726.1	c.384delG	p.Glu128AspfsTer4	frameshift_variant	Exon 4 of 5		XP_047300682.1
PDE6D	NM_001291018.2	c.265+797delG		intron_variant	Intron 3 of 3		NP_001277947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6D	ENST00000287600.9	c.342delG	p.Glu114AspfsTer4	frameshift_variant	Exon 4 of 5	1	NM_002601.4	ENSP00000287600.4
PDE6D	ENST00000428104.2	c.285delG	p.Glu95AspfsTer4	frameshift_variant	Exon 5 of 5	3		ENSP00000399098.2
PDE6D	ENST00000409772.5	c.265+797delG		intron_variant	Intron 3 of 3	3		ENSP00000387108.1
PDE6D	ENST00000486044.1	n.*206delG		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 22 Pathogenic:1

Jun 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu114Aspfs*4) in the PDE6D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the PDE6D protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PDE6D protein in which other variant(s) (p.Leu123Cysfs*13) have been determined to be pathogenic (PMID: 30423442). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with PDE6D-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-232601925;