2-231732996-C-G

Position:

• chr2-231732996-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002601.4(PDE6D):​c.409G>C​(p.Asp137His) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE6D NM_002601.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.36

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6D	NM_002601.4	c.409G>C	p.Asp137His	missense_variant	5/5	ENST00000287600.9	NP_002592.1
PDE6D	XM_047444726.1	c.451G>C	p.Asp151His	missense_variant	5/5		XP_047300682.1
PDE6D	NM_001291018.2	c.*21G>C		3_prime_UTR_variant	4/4		NP_001277947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6D	ENST00000287600.9	c.409G>C	p.Asp137His	missense_variant	5/5	1	NM_002601.4	ENSP00000287600.4
PDE6D	ENST00000409772.5	c.*21G>C		3_prime_UTR_variant	4/4	3		ENSP00000387108.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.74		Gain of sheet (P = 0.0166);
MVP		0.66
MPC		2.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.76
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs146510084; hg19: chr2-232597706;