22-20036809-T-A

Position:

• chr22-20036809-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000327374.9(TANGO2):​c.11T>A​(p.Ile4Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TANGO2 ENST00000327374.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.72

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TANGO2	NM_152906.7	c.11T>A	p.Ile4Asn	missense_variant	2/9	ENST00000327374.9	NP_690870.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TANGO2	ENST00000327374.9	c.11T>A	p.Ile4Asn	missense_variant	2/9	1	NM_152906.7	ENSP00000332721	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 4 of the TANGO2 protein (p.Ile4Asn). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 392250). This variant has not been reported in the literature in individuals affected with TANGO2-related conditions. This variant is not present in population databases (gnomAD no frequency). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2019	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;T;T;.;.;T;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	4.1	H;.;.;.;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.8	D;D;D;.;D;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D;D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;.;D;.
Vest4		0.91
MVP		0.26
MPC		0.77
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057524410; hg19: chr22-20024332;