chr22-20061538-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_152906.7(TANGO2):​c.460G>A​(p.Gly154Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000355 in 1,605,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

TANGO2
NM_152906.7 missense

Scores

8
7
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 5.99
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-20061538-G-A is Pathogenic according to our data. Variant chr22-20061538-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-20061538-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TANGO2NM_152906.7 linkc.460G>A p.Gly154Arg missense_variant Exon 7 of 9 ENST00000327374.9 NP_690870.3 Q6ICL3-1B7Z4V5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TANGO2ENST00000327374.9 linkc.460G>A p.Gly154Arg missense_variant Exon 7 of 9 1 NM_152906.7 ENSP00000332721.4 Q6ICL3-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152240
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000135
AC:
32
AN:
236834
Hom.:
0
AF XY:
0.0000625
AC XY:
8
AN XY:
128074
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000662
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000187
Gnomad OTH exome
AF:
0.00138
GnomAD4 exome
AF:
0.0000379
AC:
55
AN:
1452910
Hom.:
0
Cov.:
30
AF XY:
0.0000291
AC XY:
21
AN XY:
721848
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.000640
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000356
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152240
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.000157
AC:
19

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome Pathogenic:6Other:1
May 09, 2019
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 21, 2021
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

The p.Gly154Arg variant in TANGO2 has been reported in 7 individuals with metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) (PMID: 26805781, 29369572, 32576985) and has been identified in in 0.07% (1/33224) Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs752298579). 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. This variant has also been reported in ClinVar (Variation ID#: 208823) and has been interpreted as Pathogenic by Baylor Genetics, OMIM, GeneReviews, Undiagnosed Diseases Network (NIH), and Department of Molecular and Human Genetics (Baylor College of Medicine). In vitro functional studies provide some evidence that the p.Gly154Arg variant may impact protein function (PMID: 26805781). However, these types of assays may not accurately represent biological function. Of the 7 affected individuals, 4 of those were homozygotes and 3 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly154Arg variant is pathogenic (Variation ID: 224770; PMID: 26805781, 32576985). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. 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: PM3_very-strong, PS3_moderate (Richards 2015). -

Apr 11, 2016
Undiagnosed Diseases Network, NIH
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has been described in multiple affected individuals (PMID 26805781) -

-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The TANGO2 c.460G>A (p.Gly154Arg) variant has been reported in homozygous and compound heterozygous state in individuals affected with metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) (Lalani SR et al; 2016, Lalani SR et al; 2018 ). The p.Gly154Arg variant is reported with the allele frequency of 0.01351% in gnomad Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. The amino acid Gly at position 154 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly154Arg in TANGO2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Of the 7 affected individuals, 4 of those were homozygotes and 3 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly154Arg variant is pathogenic (Lalani SR et al; 2016). For these reasons, this variant has been classified as Pathogenic. -

Mar 29, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 16, 2020
Department of Molecular and Human Genetics, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

Common variant in persons of Hispanic ethnicity from Latin America -

not provided Pathogenic:2
Jan 01, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 154 of the TANGO2 protein (p.Gly154Arg). This variant is present in population databases (rs752298579, gnomAD 0.06%). This missense change has been observed in individual(s) with TANGO2-related conditions (PMID: 26805781). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208823). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TANGO2 function (PMID: 26805781). For these reasons, this variant has been classified as Pathogenic. -

Jun 13, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26805781, 31216405, 29369572, 32576985, 34668327) -

Cardiac arrhythmia;C0036572:Seizure;C3714756:Intellectual disability;C3807306:Acute rhabdomyolysis;C4025572:Episodic flaccid weakness Pathogenic:1
Sep 01, 2015
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing;research

Pathogenicity based on finding the variant in the homozygous state in 4 individuals, and in 1 compound heterozygote, all affected with a similar condition of recurrent rhabdomyolysis, intellectual disability, seizures, recurrent episodes of muscle weakness and metabolic crises, and cardiac arrhythmia. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Uncertain
0.030
T
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.25
.;.;.;.;.;T;.;T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.98
.;D;D;D;D;D;.;D
M_CAP
Benign
0.084
D
MetaRNN
Uncertain
0.45
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.33
T
MutationAssessor
Pathogenic
4.5
.;.;.;.;.;H;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-5.2
D;.;.;D;D;D;D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.024
D;.;.;D;D;D;D;D
Sift4G
Uncertain
0.0050
D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;D;.;D;.;.
Vest4
0.93
MVP
0.50
MPC
0.63
ClinPred
0.93
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752298579; hg19: chr22-20049061; API