2-231738020-GC-G

Variant names:

• chr2-231738020-GC-G
• rs2048717087
• NM_002601.4:c.257delG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002601.4(PDE6D):​c.257delG​(p.Cys86SerfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE6D NM_002601.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.57

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 Pathogenic. Variant got 12 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 2-231738020-GC-G is Pathogenic according to our data. Variant chr2-231738020-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 917951.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.257delG	p.Cys86SerfsTer2	frameshift_variant	Exon 3 of 5	ENST00000287600.9	NP_002592.1
PDE6D	NM_001291018.2	c.257delG	p.Cys86SerfsTer2	frameshift_variant	Exon 3 of 4		NP_001277947.1
PDE6D	XM_047444726.1	c.299delG	p.Cys100SerfsTer2	frameshift_variant	Exon 3 of 5		XP_047300682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6D	ENST00000287600.9	c.257delG	p.Cys86SerfsTer2	frameshift_variant	Exon 3 of 5	1	NM_002601.4	ENSP00000287600.4
PDE6D	ENST00000428104.2	c.200delG	p.Cys67SerfsTer2	frameshift_variant	Exon 4 of 5	3		ENSP00000399098.2
PDE6D	ENST00000409772.5	c.257delG	p.Cys86SerfsTer2	frameshift_variant	Exon 3 of 4	3		ENSP00000387108.1
PDE6D	ENST00000486044.1	n.406delG		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 22 Pathogenic:2

Apr 05, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2048717087; hg19: chr2-232602730;