2-201389826-C-T

Variant names:

• chr2-201389826-C-T
• rs140471328
• NM_015049.3:c.1168G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015049.3(TRAK2):​c.1168G>A​(p.Glu390Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: TRAK2 NM_015049.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2024351).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAK2	NM_015049.3	c.1168G>A	p.Glu390Lys	missense_variant	Exon 11 of 16	ENST00000332624.8	NP_055864.2
TRAK2	XM_047445578.1	c.1168G>A	p.Glu390Lys	missense_variant	Exon 11 of 16		XP_047301534.1
TRAK2	XM_047445579.1	c.535G>A	p.Glu179Lys	missense_variant	Exon 8 of 13		XP_047301535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAK2	ENST00000332624.8	c.1168G>A	p.Glu390Lys	missense_variant	Exon 11 of 16	1	NM_015049.3	ENSP00000328875.3
STRADB	ENST00000458269.6	c.28+1751C>T		intron_variant	Intron 1 of 5	5		ENSP00000409552.2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 250764 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135518

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000249 AC: 364 AN: 1461264 Hom.: 0 Cov.: 30 AF XY: 0.000223 AC XY: 162 AN XY: 726914

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74360

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000387 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1168G>A (p.E390K) alteration is located in exon 11 (coding exon 10) of the TRAK2 gene. This alteration results from a G to A substitution at nucleotide position 1168, causing the glutamic acid (E) at amino acid position 390 to be replaced by a lysine (K). 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	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.13
Sift	Benign	0.068	T
Sift4G	Uncertain	0.056	T
Polyphen		0.96	D
Vest4		0.40
MVP		0.35
MPC		0.50
ClinPred		0.19	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.42

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

Other links and lift over

dbSNP: rs140471328; hg19: chr2-202254549;