22-20055981-G-A

Variant names:

• chr22-20055981-G-A
• rs142442293
• NM_152906.7:c.419G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152906.7(TANGO2):​c.419G>A​(p.Arg140Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,614,098 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (59 hom.)
• Consequence: TANGO2 NM_152906.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.11
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008440733).
• BP6: Variant 22-20055981-G-A is Benign according to our data. Variant chr22-20055981-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00473 (720/152316) while in subpopulation NFE AF = 0.00725 (493/68004). AF 95% confidence interval is 0.00672. There are 4 homozygotes in GnomAd4. There are 345 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TANGO2	NM_152906.7	MANE Select	c.419G>A	p.Arg140Gln	missense	Exon 6 of 9	NP_690870.3
	TANGO2	NM_001322141.2		c.542G>A	p.Arg181Gln	missense	Exon 6 of 9	NP_001309070.1
	TANGO2	NM_001322142.2		c.419G>A	p.Arg140Gln	missense	Exon 6 of 9	NP_001309071.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TANGO2	ENST00000327374.9	TSL:1 MANE Select	c.419G>A	p.Arg140Gln	missense	Exon 6 of 9	ENSP00000332721.4	Q6ICL3-1
	TANGO2	ENST00000401833.5	TSL:5	c.542G>A	p.Arg181Gln	missense	Exon 6 of 9	ENSP00000384827.1	Q6ICL3-4
	TANGO2	ENST00000456048.5	TSL:2	c.542G>A	p.Arg181Gln	missense	Exon 6 of 9	ENSP00000403645.2	Q6ICL3-4

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 720 AN: 152198 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00725

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00600 AC: 1509 AN: 251438 AF XY: 0.00578

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00882

Gnomad OTH exome AF: 0.00765

GnomAD4 exome AF: 0.00662 AC: 9680 AN: 1461782 Hom.: 59 Cov.: 31 AF XY: 0.00643 AC XY: 4678 AN XY: 727206

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.00309 AC: 138 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86256

European-Finnish (FIN) AF: 0.0128 AC: 681 AN: 53406

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00754 AC: 8386 AN: 1111922

Other (OTH) AF: 0.00588 AC: 355 AN: 60394

GnomAD4 genome AF: 0.00473 AC: 720 AN: 152316 Hom.: 4 Cov.: 33 AF XY: 0.00463 AC XY: 345 AN XY: 74486

African (AFR) AF: 0.000962 AC: 40 AN: 41576

American (AMR) AF: 0.00366 AC: 56 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00725 AC: 493 AN: 68004

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00624 Hom.: 11

Bravo AF: 0.00413

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00692 AC: 840

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00569

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.018	D
Polyphen		0.37	B
Vest4		0.28
MVP		0.24
MPC		0.17
ClinPred		0.013	T
GERP RS		4.5
Varity_R		0.20
gMVP		0.51
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs142442293; hg19: chr22-20043504;