rs398123014
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020944.3(GBA2):c.1018C>T(p.Arg340Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,950 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_020944.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GBA2 | NM_020944.3 | c.1018C>T | p.Arg340Ter | stop_gained | 5/17 | ENST00000378103.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GBA2 | ENST00000378103.7 | c.1018C>T | p.Arg340Ter | stop_gained | 5/17 | 1 | NM_020944.3 | P1 | |
GBA2 | ENST00000378094.4 | c.1018C>T | p.Arg340Ter | stop_gained | 5/17 | 1 | |||
GBA2 | ENST00000467252.5 | n.590C>T | non_coding_transcript_exon_variant | 2/13 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251082Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135726
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461802Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727208
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 46 Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Jan 25, 2019 | This variant is interpreted as a Pathogenic for Spastic paraplegia 46, autosomal recessive. The following ACMG Tag(s) were applied: PM2 : Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3-Moderate : PS3 downgraded in strength to Moderate (PMID:26220345). PVS1 : Predicted nullvariant in a gene where LOF is a known mechanism of disease. PP1 : Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:23332917). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 07, 2013 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GBA2 are known to be pathogenic (PMID: 23332916, 23332917). This variant has been reported to affect GBA2 protein function (PMID: 26220345). This variant has been observed to segregate with clinical features of hereditary spastic paraplegia in families (PMID: 23332917). ClinVar contains an entry for this variant (Variation ID: 41489). This variant is present in population databases (rs398123014, ExAC 0.01%). This sequence change creates a premature translational stop signal (p.Arg340*) in the GBA2 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at