1-17004817-CCAGGCTGGGGAAG-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_022089.4(ATP13A2):c.348-9_351delCTTCCCCAGCCTG(p.Ser116fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_022089.4 frameshift, splice_acceptor, splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP13A2 | NM_022089.4 | c.348-9_351delCTTCCCCAGCCTG | p.Ser116fs | frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant | Exon 5 of 29 | ENST00000326735.13 | NP_071372.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250476Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135568
GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461570Hom.: 0 AF XY: 0.0000426 AC XY: 31AN XY: 727078
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74346
ClinVar
Submissions by phenotype
Kufor-Rakeb syndrome;C5567893:Autosomal recessive spastic paraplegia type 78 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 08, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 12, 2024 | This variant results in the deletion of part of exon 5 (c.348-9_351del) of the ATP13A2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP13A2 are known to be pathogenic (PMID: 16964263, 21696388). This variant is present in population databases (rs749798211, gnomAD 0.004%). This variant has been observed in individual(s) with ATP13A2-related conditions (PMID: 36065636). ClinVar contains an entry for this variant (Variation ID: 209135). 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. - |
Kufor-Rakeb syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 29, 2013 | This variant includes the the splice acceptor site of intron 4 and the first four nucleotides of exon 5. Because the splice acceptor site is deleted, it is categorized as deleterious according to ACMG guidelines (PMID:18414213). Found with another missense variant (G315R; phase undetermined) in a 54-year-old male with seizures, apraxia, progressive cognitive problems, confusion, speech difficulty, history of stroke. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 30, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at