2-231737295-G-A

Variant names:

• chr2-231737295-G-A
• NM_002601.4:c.266-3C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002601.4(PDE6D):​c.266-3C>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,409,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PDE6D NM_002601.4 splice_region, intron
• Scores: Splicing: ADA: 0.9801
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.68

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6D	NM_002601.4	c.266-3C>T		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000287600.9	NP_002592.1
PDE6D	NM_001291018.2	c.265+718C>T		intron_variant	Intron 3 of 3		NP_001277947.1
PDE6D	XM_047444726.1	c.308-3C>T		splice_region_variant, intron_variant	Intron 3 of 4		XP_047300682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6D	ENST00000287600.9	c.266-3C>T		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_002601.4	ENSP00000287600.4
PDE6D	ENST00000428104.2	c.209-3C>T		splice_region_variant, intron_variant	Intron 4 of 4	3		ENSP00000399098.2
PDE6D	ENST00000409772.5	c.265+718C>T		intron_variant	Intron 3 of 3	3		ENSP00000387108.1
PDE6D	ENST00000486044.1	n.*127C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1409560 Hom.: 0 Cov.: 23 AF XY: 0.00000142 AC XY: 1 AN XY: 704334

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: 9.39e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 22 Uncertain:1

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 1354430). 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). This sequence change falls in intron 3 of the PDE6D gene. It does not directly change the encoded amino acid sequence of the PDE6D protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.060		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: chr2-232602005;