22-20036808-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152906.7(TANGO2):c.10A>C(p.Ile4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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. I4N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TANGO2 NM_152906.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22688922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TANGO2	NM_152906.7	c.10A>C	p.Ile4Leu	missense_variant	2/9	ENST00000327374.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TANGO2	ENST00000327374.9	c.10A>C	p.Ile4Leu	missense_variant	2/9	1	NM_152906.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2023

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. This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the TANGO2 protein (p.Ile4Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TANGO2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1524823). 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 tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Benign	0.95
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.;L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.96	N;N;N;.;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.40	T;T;T;.;T;T;T;T
Sift4G	Benign	0.55	T;T;T;T;T;T;T;T
Polyphen		0.60	P;.;.;B;P;.;B;.
Vest4		0.34
MutPred		0.69		Gain of ubiquitination at K7 (P = 0.1103);Gain of ubiquitination at K7 (P = 0.1103);Gain of ubiquitination at K7 (P = 0.1103);Gain of ubiquitination at K7 (P = 0.1103);Gain of ubiquitination at K7 (P = 0.1103);Gain of ubiquitination at K7 (P = 0.1103);Gain of ubiquitination at K7 (P = 0.1103);Gain of ubiquitination at K7 (P = 0.1103);
MVP		0.040
MPC		0.14
ClinPred		0.39	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-20024331;