2-12718513-C-A

Variant summary

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

The NM_021643.4(TRIB2):​c.206C>A​(p.Pro69His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TRIB2
NM_021643.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
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 GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRIB2NM_021643.4 linkuse as main transcriptc.206C>A p.Pro69His missense_variant 1/3 ENST00000155926.9
TRIB2NR_027303.2 linkuse as main transcriptn.75+1503C>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.206C>A p.Pro69His missense_variant 1/31 NM_021643.4 P1
TRIB2ENST00000405331.3 linkuse as main transcriptc.206C>A p.Pro69His missense_variant 1/32
TRIB2ENST00000381465.2 linkuse as main transcriptc.-139+1503C>A intron_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152196
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461886
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727242
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74352
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

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 GeneticsFeb 27, 2024The c.206C>A (p.P69H) alteration is located in exon 1 (coding exon 1) of the TRIB2 gene. This alteration results from a C to A substitution at nucleotide position 206, causing the proline (P) at amino acid position 69 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
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.81
T;D
M_CAP
Benign
0.043
D
MetaRNN
Uncertain
0.54
D;D
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
0.55
N;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.26
Sift
Benign
0.19
T;T
Sift4G
Benign
0.17
T;T
Polyphen
0.98
D;.
Vest4
0.69
MutPred
0.44
Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP
0.41
MPC
1.9
ClinPred
0.97
D
GERP RS
5.2
Varity_R
0.36
gMVP
0.42

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: rs755829009; hg19: chr2-12858639; API