chr2-231738139-C-T

Position:

• chr2-231738139-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002601.4(PDE6D):​c.140-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE6D NM_002601.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.27593818 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.4, offset of -32, new splice context is: gtcctgtggttttcatttAGaaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-231738139-C-T is Pathogenic according to our data. Variant chr2-231738139-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 100773.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-231738139-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6D	NM_002601.4	c.140-1G>A		splice_acceptor_variant		ENST00000287600.9	NP_002592.1
PDE6D	NM_001291018.2	c.140-1G>A		splice_acceptor_variant			NP_001277947.1
PDE6D	XM_047444726.1	c.182-1G>A		splice_acceptor_variant			XP_047300682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6D	ENST00000287600.9	c.140-1G>A		splice_acceptor_variant		1	NM_002601.4	ENSP00000287600	P1
PDE6D	ENST00000409772.5	c.140-1G>A		splice_acceptor_variant		3		ENSP00000387108
PDE6D	ENST00000428104.2	c.83-1G>A		splice_acceptor_variant		3		ENSP00000399098
PDE6D	ENST00000486044.1	n.289-1G>A		splice_acceptor_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Joubert syndrome 22 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.78		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777156; hg19: chr2-232602849;