chr2-201389447-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_015049.3(TRAK2):c.1250G>A(p.Arg417His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )
Consequence
TRAK2
NM_015049.3 missense
NM_015049.3 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 2.09
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.047861576).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TRAK2 | NM_015049.3 | c.1250G>A | p.Arg417His | missense_variant | 12/16 | ENST00000332624.8 | |
| TRAK2 | XM_047445578.1 | c.1250G>A | p.Arg417His | missense_variant | 12/16 | ||
| TRAK2 | XM_047445579.1 | c.617G>A | p.Arg206His | missense_variant | 9/13 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TRAK2 | ENST00000332624.8 | c.1250G>A | p.Arg417His | missense_variant | 12/16 | 1 | NM_015049.3 | P1 | |
| STRADB | ENST00000458269.6 | c.28+1372C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000994 AC: 25AN: 251420Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135892
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GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 727242
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GnomAD4 genome 0.0000460 AC: 7AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74288
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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 submitter | clinical testing | Ambry Genetics | Dec 19, 2022 | The c.1250G>A (p.R417H) alteration is located in exon 12 (coding exon 11) of the TRAK2 gene. This alteration results from a G to A substitution at nucleotide position 1250, causing the arginine (R) at amino acid position 417 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at