rs397515335
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006642.5(SDCCAG8):c.1420del(p.Glu474SerfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
SDCCAG8
NM_006642.5 frameshift
NM_006642.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.29
Genes affected
SDCCAG8 (HGNC:10671): (SHH signaling and ciliogenesis regulator SDCCAG8) This gene encodes a centrosome associated protein. This protein may be involved in organizing the centrosome during interphase and mitosis. Mutations in this gene are associated with retinal-renal ciliopathy. [provided by RefSeq, Oct 2010]
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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 1-243344276-AG-A is Pathogenic according to our data. Variant chr1-243344276-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 57.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-243344276-AG-A is described in Lovd as [Pathogenic]. Variant chr1-243344276-AG-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDCCAG8 | NM_006642.5 | c.1420del | p.Glu474SerfsTer20 | frameshift_variant | 12/18 | ENST00000366541.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDCCAG8 | ENST00000366541.8 | c.1420del | p.Glu474SerfsTer20 | frameshift_variant | 12/18 | 1 | NM_006642.5 | P1 | |
SDCCAG8 | ENST00000435549.1 | c.760del | p.Glu254SerfsTer20 | frameshift_variant | 7/11 | 1 | |||
SDCCAG8 | ENST00000493334.1 | n.387del | non_coding_transcript_exon_variant | 3/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251312Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135832
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461708Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727164
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Senior-Loken syndrome 7;C3889474:Bardet-Biedl syndrome 16 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 04, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2023 | This premature translational stop signal has been observed in individual(s) with Senior-Loken syndrome (PMID: 20835237). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 57). This variant is present in population databases (rs770467138, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Glu474Serfs*20) in the SDCCAG8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDCCAG8 are known to be pathogenic (PMID: 20835237, 22190896). - |
Bardet-Biedl syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 03, 2023 | Variant summary: SDCCAG8 c.1420delG (p.Glu474SerfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251312 control chromosomes (gnomAD). c.1420delG has been reported in the literature in multiple individuals affected with nephronophthisis and retinal degeneration (Senior-Loken syndrome), including at least three homozygous individuals from two unrelated families (e.g. Otto_2010, Halbritter_2013, Al Alawi_2019). These data indicate that the variant is very likely to be associated with disease. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Senior-Loken syndrome 7 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2010 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2019 | 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: 22190896, 21866095, 20835237, 31844813) - |
Computational scores
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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