rs762152984
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The ENST00000371447.4(PDE6C):āc.836T>Cā(p.Ile279Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000068 ( 0 hom. )
Consequence
PDE6C
ENST00000371447.4 missense
ENST00000371447.4 missense
Scores
2
12
5
Clinical Significance
Conservation
PhyloP100: 6.18
Genes affected
PDE6C (HGNC:8787): (phosphodiesterase 6C) This gene encodes the alpha-prime subunit of cone phosphodiesterase, which is composed of a homodimer of two alpha-prime subunits and 3 smaller proteins of 11, 13, and 15 kDa. Mutations in this gene are associated with cone dystrophy type 4 (COD4). [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a domain GAF 2 (size 177) in uniprot entity PDE6C_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in ENST00000371447.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.883
PP5
Variant 10-93622044-T-C is Pathogenic according to our data. Variant chr10-93622044-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 487697.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr10-93622044-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PDE6C | NM_006204.4 | c.836T>C | p.Ile279Thr | missense_variant | 4/22 | ENST00000371447.4 | NP_006195.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PDE6C | ENST00000371447.4 | c.836T>C | p.Ile279Thr | missense_variant | 4/22 | 1 | NM_006204.4 | ENSP00000360502 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251366Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135850
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461780Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727194
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Achromatopsia 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2019 | - - |
Achromatopsia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Molecular Genetics Laboratory, Institute for Ophthalmic Research | Dec 01, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | This variant is present in population databases (rs762152984, gnomAD 0.004%). This missense change has been observed in individual(s) with achromatopsia (PMID: 30080950). ClinVar contains an entry for this variant (Variation ID: 487697). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDE6C protein function. 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. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 279 of the PDE6C protein (p.Ile279Thr). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of stability (P = 0.0038);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at