chr22-20036832-CCT-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_152906.7(TANGO2):c.35_36del(p.Pro12ArgfsTer16) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000124 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P12P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TANGO2
NM_152906.7 frameshift
NM_152906.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.63
Genes affected
TANGO2 (HGNC:25439): (transport and golgi organization 2 homolog) This gene belongs to the transport and Golgi organization family, whose members are predicted to play roles in secretory protein loading in the endoplasmic reticulum. Depletion of this gene in Drosophila S2 cells causes fusion of the Golgi with the ER. In mouse tissue culture cells, this protein co-localizes with a mitochondrially targeted mCherry protein and displays very low levels of co-localization with Golgi and peroxisomes. Allelic variants of this gene are associated with rhabdomyolysis, metabolic crises with encephalopathy, and cardiac arrhythmia. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 22-20036832-CCT-C is Pathogenic according to our data. Variant chr22-20036832-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 817318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TANGO2 | NM_152906.7 | c.35_36del | p.Pro12ArgfsTer16 | frameshift_variant | 2/9 | ENST00000327374.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TANGO2 | ENST00000327374.9 | c.35_36del | p.Pro12ArgfsTer16 | frameshift_variant | 2/9 | 1 | NM_152906.7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461892Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727248
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74374
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2019 | The c.35_36delCT variant in the TANGO2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.35_36delCT variant causes a frameshift starting with codon Proline 12, changes this amino acid to a Arginine residue, and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Pro12ArgfsX16. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.35_36delCT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.35_36delCT as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817318). This premature translational stop signal has been observed in individual(s) with TANGO2-related conditions (PMID: 33845444). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro12Argfs*16) in the TANGO2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TANGO2 are known to be pathogenic (PMID: 26805781, 26805782). - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at