2-201399433-C-T

Position:

• chr2-201399433-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000332624.8(TRAK2):​c.424G>A​(p.Val142Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 1,610,932 control chromosomes in the GnomAD database, including 347,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.57 (25978 hom., cov: 32)
  • Exomes 𝑓: 0.66 (321491 hom.)
• Consequence: TRAK2 ENST00000332624.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.022073E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAK2	NM_015049.3	c.424G>A	p.Val142Ile	missense_variant	5/16	ENST00000332624.8	NP_055864.2
TRAK2	XM_047445578.1	c.424G>A	p.Val142Ile	missense_variant	5/16		XP_047301534.1
TRAK2	XM_047445579.1	c.-210G>A		5_prime_UTR_variant	2/13		XP_047301535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAK2	ENST00000332624.8	c.424G>A	p.Val142Ile	missense_variant	5/16	1	NM_015049.3	ENSP00000328875	P1
TRAK2	ENST00000430254.1	c.424G>A	p.Val142Ile	missense_variant	5/8	2		ENSP00000409333
STRADB	ENST00000458269.6	c.28+11358C>T		intron_variant		5		ENSP00000409552
TRAK2	ENST00000486291.1	n.78G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86618 AN: 151742 Hom.: 25981 Cov.: 32

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.676

Gnomad OTH AF: 0.562

GnomAD3 exomes AF: 0.621 AC: 155647 AN: 250676 Hom.: 49566 AF XY: 0.633 AC XY: 85794 AN XY: 135480

Gnomad AFR exome AF: 0.367

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.616

Gnomad EAS exome AF: 0.502

Gnomad SAS exome AF: 0.686

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.674

Gnomad OTH exome AF: 0.624

GnomAD4 exome AF: 0.660 AC: 962762 AN: 1459072 Hom.: 321491 Cov.: 43 AF XY: 0.662 AC XY: 480680 AN XY: 725750

Gnomad4 AFR exome AF: 0.359

Gnomad4 AMR exome AF: 0.555

Gnomad4 ASJ exome AF: 0.619

Gnomad4 EAS exome AF: 0.450

Gnomad4 SAS exome AF: 0.688

Gnomad4 FIN exome AF: 0.649

Gnomad4 NFE exome AF: 0.682

Gnomad4 OTH exome AF: 0.635

GnomAD4 genome AF: 0.570 AC: 86616 AN: 151860 Hom.: 25978 Cov.: 32 AF XY: 0.570 AC XY: 42319 AN XY: 74220

Gnomad4 AFR AF: 0.377

Gnomad4 AMR AF: 0.559

Gnomad4 ASJ AF: 0.630

Gnomad4 EAS AF: 0.486

Gnomad4 SAS AF: 0.685

Gnomad4 FIN AF: 0.646

Gnomad4 NFE AF: 0.676

Gnomad4 OTH AF: 0.565

Alfa AF: 0.654 Hom.: 79103

Bravo AF: 0.549

TwinsUK AF: 0.683 AC: 2534

ALSPAC AF: 0.693 AC: 2671

ESP6500AA AF: 0.374 AC: 1648

ESP6500EA AF: 0.673 AC: 5787

ExAC AF: 0.623 AC: 75574

Asia WGS AF: 0.567 AC: 1973 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.000030	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.92	L;L
MutationTaster	Benign	0.91	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.046
Sift	Benign	0.45	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0030	B;.
Vest4		0.079
MPC		0.098
ClinPred		0.0060	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.094

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

Other links and lift over

dbSNP: rs13022344; hg19: chr2-202264156; COSMIC: COSV60271647;