rs142442293

Positions:

• chr22-20055981-G-A
• chr22-20055981-G-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TANGO2	NM_152906.7	c.419G>A	p.Arg140Gln	missense_variant	6/9	ENST00000327374.9	NP_690870.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TANGO2	ENST00000327374.9	c.419G>A	p.Arg140Gln	missense_variant	6/9	1	NM_152906.7	ENSP00000332721	P1

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

GnomAD3 exomes AF: 0.00600 AC: 1509 AN: 251438 Hom.: 14 AF XY: 0.00578 AC XY: 785 AN XY: 135892

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 SAS exome AF: 0.000523

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

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.00754

Gnomad4 OTH exome AF: 0.00588

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

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.00725

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00643 Hom.: 7

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TANGO2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;.;D
MetaRNN	Benign	0.0084	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N;.;.;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.013	D;.;.;T;T;T;T
Sift4G	Uncertain	0.018	D;T;D;D;T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs142442293; hg19: chr22-20043504;