rs372949028
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_152906.7(TANGO2):c.605+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,546,486 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 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
TANGO2
NM_152906.7 splice_donor
NM_152906.7 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.71
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 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6, offset of 23, new splice context is: gggGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift 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 22-20061684-G-A is Pathogenic according to our data. Variant chr22-20061684-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208824.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.605+1G>A | splice_donor_variant | ENST00000327374.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TANGO2 | ENST00000327374.9 | c.605+1G>A | splice_donor_variant | 1 | NM_152906.7 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152246Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000713 AC: 11AN: 154196Hom.: 0 AF XY: 0.000111 AC XY: 9AN XY: 81122
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GnomAD4 exome AF: 0.0000251 AC: 35AN: 1394122Hom.: 0 Cov.: 30 AF XY: 0.0000364 AC XY: 25AN XY: 686908
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152364Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74510
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome Pathogenic:4
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 09, 2019 | - - |
| Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 21, 2021 | The c.605+1G>A variant in TANGO2 has been reported in 2 individuals with metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) (PMID: 26805781, 29891059) and has been identified in in 0.04% (8/22394) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs372949028). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of the 2 affected individuals, 1 of those was a homozygote, and one was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the c.605+1G>A variant is pathogenic (Variation ID: 208823; PMID: 26805781, 29891059). This variant has also been reported in ClinVar (Variation ID#: 208824) and has been interpreted as likely pathogenic/pathogenic by Kariminejad - Najmabadi Pathology & Genetics Center, Baylor Genetics, Rady Children's Institute for Genomic Medicine (Rady Children's Hospital San Diego), OMIM, and GeneReviews. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the TANGO2 gene is a strongly established disease mechanism in autosomal recessive MECRCN. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive MECRCN. ACMG/AMP Criteria applied: PVS1_strong, PM3 (Richards 2015). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Jan 27, 2017 | The c.605+1G>A variant is a canonical splice site variant that is predicted to result in aberrant splicing. It has been previously reported in the homozygous state in a patient with MECRCN (PMID: 26805781). This variant has been reported in one Latino and five South Asian individuals in the ExAC database, with an overall allele frequency of 0.0003192. Thus it is presumed to be rare. This genomic position is well conserved. Based on the combined evidence, the c.605+1G>A variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Institute of Human Genetics, University of Ulm | Oct 19, 2022 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 11, 2023 | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30650451, 31980526, 26805781) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change affects a donor splice site in intron 7 of the TANGO2 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 TANGO2 are known to be pathogenic (PMID: 26805781, 26805782). This variant is present in population databases (rs372949028, gnomAD 0.04%). Disruption of this splice site has been observed in individuals with clinical features of TANGO2-related conditions (PMID: 26805781, 30650451; Invitae). ClinVar contains an entry for this variant (Variation ID: 208824). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Abnormality of metabolism/homeostasis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Cardiac arrhythmia;C0036572:Seizure;C3714756:Intellectual disability;C3807306:Acute rhabdomyolysis;C4025572:Episodic flaccid weakness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2015 | Pathogenicity based on finding it once homozygous in a 1-year-old male with episodic metabolic crises, developmental delay, hypotonia - |
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
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -3
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at