rs752298579

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV001999936: "In vitro functional studies provide some evidence that the p.Gly154Arg variant may impact protein function." PMID:26805781" and additional evidence is available in ClinVar.

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

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

TANGO2 links:

ENSG00000236540 (HGNC:41096):

ENSG00000236540 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001999936: "In vitro functional studies provide some evidence that the p.Gly154Arg variant may impact protein function." PMID: 26805781; SCV002215019: Experimental studies have shown that this missense change affects TANGO2 function (PMID: 26805781).

PP5

Variant 22-20061538-G-A is Pathogenic according to our data. Variant chr22-20061538-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152906.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TANGO2	NM_152906.7	MANE Select	c.460G>A	p.Gly154Arg	missense	Exon 7 of 9	NP_690870.3
TANGO2	NM_001322141.2		c.583G>A	p.Gly195Arg	missense	Exon 7 of 9	NP_001309070.1
TANGO2	NM_001322142.2		c.460G>A	p.Gly154Arg	missense	Exon 7 of 9	NP_001309071.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TANGO2	ENST00000327374.9	TSL:1 MANE Select	c.460G>A	p.Gly154Arg	missense	Exon 7 of 9	ENSP00000332721.4	Q6ICL3-1
TANGO2	ENST00000401833.5	TSL:5	c.583G>A	p.Gly195Arg	missense	Exon 7 of 9	ENSP00000384827.1	Q6ICL3-4
TANGO2	ENST00000456048.5	TSL:2	c.583G>A	p.Gly195Arg	missense	Exon 7 of 9	ENSP00000403645.2	Q6ICL3-4

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

GnomAD2 exomes

AF:

0.000135

AC:

AN:

236834

AF XY:

0.0000625

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 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

African (AFR)

AF:

0.0000300

AC:

AN:

33384

American (AMR)

AF:

0.000640

AC:

AN:

43750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25694

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.0000356

AC:

AN:

84348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5040

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1108632

Other (OTH)

AF:

0.00

AC:

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000157

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome (7)

not provided (2)

Cardiac arrhythmia;C0036572:Seizure;C3714756:Intellectual disability;C3807306:Acute rhabdomyolysis;C4025572:Episodic flaccid weakness (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

4.5

PhyloP100

6.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.54

Sift

Uncertain

0.024

Sift4G

Uncertain

0.0050

Polyphen

1.0

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

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over