chr22-20061538-G-A

Variant names:

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

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]

TANGO2 links:

ENSG00000236540 (HGNC:):

ENSG00000236540 links:

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
TANGO2	NM_152906.7 link	c.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
TANGO2	ENST00000327374.9 link	c.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:

AN:

152240

Hom.:

Cov.:

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:

AN:

236834

Hom.:

AF XY:

0.0000625

AC XY:

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:

AN:

1452910

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

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:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

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:

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

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 21, 2021	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Apr 11, 2016	This variant has been described in multiple affected individuals (PMID 26805781) -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 09, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	Common variant in persons of Hispanic ethnicity from Latin America -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular and Human Genetics, Baylor College of Medicine	Apr 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 29, 2024	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2025	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2024	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

Pathogenic, criteria provided, single submitter

clinical testing;research

Baylor Genetics

Sep 01, 2015

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

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

.;.;.;.;.;T;.;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

.;D;D;D;D;D;.;D

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.45

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

4.5

.;.;.;.;.;H;.;.

PrimateAI

Uncertain

0.70

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over