rs61749670
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000180.4(GUCY2D):c.389del(p.Pro130LeufsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000264 in 1,515,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000022 ( 0 hom. )
Consequence
GUCY2D
NM_000180.4 frameshift
NM_000180.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.661
Genes affected
GUCY2D (HGNC:4689): (guanylate cyclase 2D, retinal) This gene encodes a retina-specific guanylate cyclase, which is a member of the membrane guanylyl cyclase family. Like other membrane guanylyl cyclases, this enzyme has a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, this enzyme is not activated by natriuretic peptides. Mutations in this gene result in Leber congenital amaurosis and cone-rod dystrophy-6 diseases. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-8003433-AC-A is Pathogenic according to our data. Variant chr17-8003433-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 98602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8003433-AC-A is described in Lovd as [Pathogenic]. Variant chr17-8003433-AC-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GUCY2D | NM_000180.4 | c.389del | p.Pro130LeufsTer36 | frameshift_variant | 2/20 | ENST00000254854.5 | |
GUCY2D | XM_011523816.2 | c.389del | p.Pro130LeufsTer36 | frameshift_variant | 1/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GUCY2D | ENST00000254854.5 | c.389del | p.Pro130LeufsTer36 | frameshift_variant | 2/20 | 1 | NM_000180.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151914Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000174 AC: 2AN: 115224Hom.: 0 AF XY: 0.0000157 AC XY: 1AN XY: 63744
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GnomAD4 exome AF: 0.00000220 AC: 3AN: 1363664Hom.: 0 Cov.: 34 AF XY: 0.00000149 AC XY: 1AN XY: 672966
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Leber congenital amaurosis 1 Pathogenic:3
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | - | - - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24265693, 8944027, 20683928, 20604683, 31814694, 32865313, 31736247, 32094338) - |
Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change creates a premature translational stop signal (p.Pro130Leufs*36) in the GUCY2D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GUCY2D are known to be pathogenic (PMID: 10951519, 11328726). This variant is present in population databases (rs61749670, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Leber congenital amaurosis (PMID: 8944027, 20683928). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98602). For these reasons, this variant has been classified as Pathogenic. - |
Leber congenital amaurosis Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1;C4551884:Choroidal dystrophy, central areolar, 1;C5231408:Night blindness, congenital stationary, type1i Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 30, 2021 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at