2-12740417-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021643.4(TRIB2):​c.655G>A​(p.Val219Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

TRIB2
NM_021643.4 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
TRIB2 (HGNC:30809): (tribbles pseudokinase 2) This gene encodes one of three members of the Tribbles family. The Tribbles members share a Trb domain, which is homologous to protein serine-threonine kinases, but lacks the active site lysine and probably lacks a catalytic function. The Tribbles proteins interact and modulate the activity of signal transduction pathways in a number of physiological and pathological processes. This Tribbles member induces apoptosis of cells mainly of the hematopoietic origin. It has been identified as a protein up-regulated by inflammatory stimuli in myeloid (THP-1) cells, and also as an oncogene that inactivates the transcription factor C/EBPalpha (CCAAT/enhancer-binding protein alpha) and causes acute myelogenous leukemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 48 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRIB2NM_021643.4 linkuse as main transcriptc.655G>A p.Val219Ile missense_variant 3/3 ENST00000155926.9
TRIB2NR_027303.2 linkuse as main transcriptn.460G>A non_coding_transcript_exon_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TRIB2ENST00000155926.9 linkuse as main transcriptc.655G>A p.Val219Ile missense_variant 3/31 NM_021643.4 P1
TRIB2ENST00000381465.2 linkuse as main transcriptc.247G>A p.Val83Ile missense_variant 3/32

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251424
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000328
AC:
48
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.0000261
AC XY:
19
AN XY:
727246
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000414
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152138
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000986
Hom.:
0
Bravo
AF:
0.0000264

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 07, 2022The c.655G>A (p.V219I) alteration is located in exon 3 (coding exon 3) of the TRIB2 gene. This alteration results from a G to A substitution at nucleotide position 655, causing the valine (V) at amino acid position 219 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Benign
-0.050
T
BayesDel_noAF
Benign
-0.13
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.058
D
MetaRNN
Uncertain
0.50
T;T
MetaSVM
Uncertain
0.021
D
MutationAssessor
Benign
1.3
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.98
N;N
REVEL
Uncertain
0.44
Sift
Uncertain
0.0030
D;T
Sift4G
Benign
0.062
T;T
Polyphen
1.0
D;.
Vest4
0.37
MVP
0.62
MPC
1.8
ClinPred
0.83
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.21
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs925303861; hg19: chr2-12880543; COSMIC: COSV105843862; COSMIC: COSV105843862; API