rs756907665
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_006642.5(SDCCAG8):c.546+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00000496 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
SDCCAG8
NM_006642.5 splice_donor
NM_006642.5 splice_donor
Scores
5
1
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 6.08
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 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.029178338 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 1-243286398-G-A is Pathogenic according to our data. Variant chr1-243286398-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 566217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDCCAG8 | NM_006642.5 | c.546+1G>A | splice_donor_variant | ENST00000366541.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDCCAG8 | ENST00000366541.8 | c.546+1G>A | splice_donor_variant | 1 | NM_006642.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250870Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135762
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461526Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727068
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
SDCCAG8-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 28, 2023 | The SDCCAG8 c.546+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0063% of alleles in individuals of African descent in gnomAD. Loss of function variants in SDCCAG8 are a known mechanism of disease (see for example Otto et al. 2010. PubMed ID: 20835237; Chaki et al. 2011. PubMed ID: 21866095). Based on the available evidence, we consider the SDCCAG8 c.546+1G>A variant to be likely pathogenic. - |
Senior-Loken syndrome 7;C3889474:Bardet-Biedl syndrome 16 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 11, 2017 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDCCAG8 are known to be pathogenic (PMID: 20835237). This variant has not been reported in the literature in individuals with SDCCAG8-related disease. This variant is present in population databases (rs756907665, ExAC 0.01%). This sequence change affects a donor splice site in intron 5 of the SDCCAG8 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at