2-201392996-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015049.3(TRAK2):ā€‹c.1026A>Cā€‹(p.Glu342Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,540 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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TRAK2
NM_015049.3 missense

Scores

2
10
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.324
Variant links:
Genes affected
TRAK2 (HGNC:13206): (trafficking kinesin protein 2) Predicted to enable GABA receptor binding activity and myosin binding activity. Predicted to be involved in several processes, including mitochondrion distribution; organelle transport along microtubule; and protein targeting. Predicted to be located in cytoplasm and plasma membrane. Predicted to be active in cytoplasmic vesicle; dendrite; and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]
STRADB (HGNC:13205): (STE20 related adaptor beta) This gene encodes a protein that belongs to the serine/threonine protein kinase STE20 subfamily. One of the active site residues in the protein kinase domain of this protein is altered, and it is thus a pseudokinase. This protein is a component of a complex involved in the activation of serine/threonine kinase 11, a master kinase that regulates cell polarity and energy-generating metabolism. This complex regulates the relocation of this kinase from the nucleus to the cytoplasm, and it is essential for G1 cell cycle arrest mediated by this kinase. The protein encoded by this gene can also interact with the X chromosome-linked inhibitor of apoptosis protein, and this interaction enhances the anti-apoptotic activity of this protein via the JNK1 signal transduction pathway. Two pseudogenes, located on chromosomes 1 and 7, have been found for this gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TRAK2NM_015049.3 linkc.1026A>C p.Glu342Asp missense_variant 10/16 ENST00000332624.8 NP_055864.2 O60296-1
TRAK2XM_047445578.1 linkc.1026A>C p.Glu342Asp missense_variant 10/16 XP_047301534.1
TRAK2XM_047445579.1 linkc.393A>C p.Glu131Asp missense_variant 7/13 XP_047301535.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TRAK2ENST00000332624.8 linkc.1026A>C p.Glu342Asp missense_variant 10/161 NM_015049.3 ENSP00000328875.3 O60296-1
STRADBENST00000458269.6 linkc.28+4921T>G intron_variant 5 ENSP00000409552.2 C9JSU7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461540
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727084
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 GeneticsOct 29, 2024The c.1026A>C (p.E342D) alteration is located in exon 10 (coding exon 9) of the TRAK2 gene. This alteration results from a A to C substitution at nucleotide position 1026, causing the glutamic acid (E) at amino acid position 342 to be replaced by an aspartic acid (D). 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
0.59
BayesDel_addAF
Uncertain
0.052
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.071
T
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.017
T
MetaRNN
Pathogenic
0.82
D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.4
N
REVEL
Benign
0.24
Sift
Uncertain
0.0050
D
Sift4G
Uncertain
0.0090
D
Polyphen
1.0
D
Vest4
0.86
MutPred
0.71
Loss of phosphorylation at S343 (P = 0.1823);
MVP
0.19
MPC
0.53
ClinPred
0.96
D
GERP RS
1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.39
gMVP
0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-202257719; API