rs146510084

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002601.4(PDE6D):​c.409G>T​(p.Asp137Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D137N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PDE6D
NM_002601.4 missense

Scores

9
7
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.36
Variant links:
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]

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ACMG classification

Classification made for transcript

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, 0.935

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PDE6DNM_002601.4 linkc.409G>T p.Asp137Tyr missense_variant Exon 5 of 5 ENST00000287600.9 NP_002592.1 O43924Q6IB24
PDE6DXM_047444726.1 linkc.451G>T p.Asp151Tyr missense_variant Exon 5 of 5 XP_047300682.1
PDE6DNM_001291018.2 linkc.*21G>T 3_prime_UTR_variant Exon 4 of 4 NP_001277947.1 O43924B8ZZK5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PDE6DENST00000287600.9 linkc.409G>T p.Asp137Tyr missense_variant Exon 5 of 5 1 NM_002601.4 ENSP00000287600.4 O43924
PDE6DENST00000409772 linkc.*21G>T 3_prime_UTR_variant Exon 4 of 4 3 ENSP00000387108.1 B8ZZK5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1459928
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
726478
show subpopulations
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D
M_CAP
Benign
0.034
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Uncertain
0.13
D
MutationAssessor
Uncertain
2.6
M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.8
D
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.80
MutPred
0.79
Gain of sheet (P = 0.0477);
MVP
0.70
MPC
2.3
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.89
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
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: chr2-232597706; API