2-12718537-G-A

Variant summary

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

The NM_021643.4(TRIB2):​c.230G>A​(p.Arg77His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TRIB2
NM_021643.4 missense

Scores

5
10
4

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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRIB2NM_021643.4 linkuse as main transcriptc.230G>A p.Arg77His missense_variant 1/3 ENST00000155926.9
TRIB2NR_027303.2 linkuse as main transcriptn.75+1527G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TRIB2ENST00000155926.9 linkuse as main transcriptc.230G>A p.Arg77His missense_variant 1/31 NM_021643.4 P1
TRIB2ENST00000405331.3 linkuse as main transcriptc.230G>A p.Arg77His missense_variant 1/32
TRIB2ENST00000381465.2 linkuse as main transcriptc.-139+1527G>A intron_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 GeneticsNov 09, 2023The c.230G>A (p.R77H) alteration is located in exon 1 (coding exon 1) of the TRIB2 gene. This alteration results from a G to A substitution at nucleotide position 230, causing the arginine (R) at amino acid position 77 to be replaced by a histidine (H). 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
Benign
0.33
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.56
D;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.050
D
MetaRNN
Uncertain
0.60
D;D
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Benign
2.0
M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.2
D;D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.038
D;D
Polyphen
1.0
D;.
Vest4
0.60
MutPred
0.61
Loss of methylation at R77 (P = 0.0399);Loss of methylation at R77 (P = 0.0399);
MVP
0.83
MPC
2.1
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.47
gMVP
0.64

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: rs1027846381; hg19: chr2-12858663; API