2-201387889-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_015049.3(TRAK2):​c.1510G>A​(p.Ala504Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,614,172 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 3 hom. )

Consequence

TRAK2
NM_015049.3 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.27
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.043789953).
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TRAK2NM_015049.3 linkuse as main transcriptc.1510G>A p.Ala504Thr missense_variant 13/16 ENST00000332624.8 NP_055864.2 O60296-1
TRAK2XM_047445578.1 linkuse as main transcriptc.1510G>A p.Ala504Thr missense_variant 13/16 XP_047301534.1
TRAK2XM_047445579.1 linkuse as main transcriptc.877G>A p.Ala293Thr missense_variant 10/13 XP_047301535.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TRAK2ENST00000332624.8 linkuse as main transcriptc.1510G>A p.Ala504Thr missense_variant 13/161 NM_015049.3 ENSP00000328875.3 O60296-1
STRADBENST00000458269 linkuse as main transcriptc.-159C>T 5_prime_UTR_variant 1/65 ENSP00000409552.2 C9JSU7

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000223
AC:
56
AN:
251054
Hom.:
0
AF XY:
0.000251
AC XY:
34
AN XY:
135672
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000894
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00111
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000121
AC:
177
AN:
1461886
Hom.:
3
Cov.:
33
AF XY:
0.000168
AC XY:
122
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000612
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000405
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152286
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000830
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000156
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.000247
AC:
30
Asia WGS
AF:
0.000578
AC:
2
AN:
3476
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

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 10, 2024The c.1510G>A (p.A504T) alteration is located in exon 13 (coding exon 12) of the TRAK2 gene. This alteration results from a G to A substitution at nucleotide position 1510, causing the alanine (A) at amino acid position 504 to be replaced by a threonine (T). 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
0.082
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.44
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.019
T
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.044
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.59
N
REVEL
Benign
0.047
Sift
Benign
0.19
T
Sift4G
Benign
0.062
T
Polyphen
0.84
P
Vest4
0.23
MutPred
0.16
Loss of MoRF binding (P = 0.144);
MVP
0.19
MPC
0.41
ClinPred
0.17
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.068
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs556634625; hg19: chr2-202252612; COSMIC: COSV60276029; API