chr2-201384127-T-G

Position:

• chr2-201384127-T-G

Variant summary

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

The NM_015049.3(TRAK2):​c.2053A>C​(p.Thr685Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRAK2 NM_015049.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAK2	NM_015049.3	c.2053A>C	p.Thr685Pro	missense_variant	15/16	ENST00000332624.8
TRAK2	XM_047445578.1	c.2053A>C	p.Thr685Pro	missense_variant	15/16
TRAK2	XM_047445579.1	c.1420A>C	p.Thr474Pro	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAK2	ENST00000332624.8	c.2053A>C	p.Thr685Pro	missense_variant	15/16	1	NM_015049.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.2053A>C (p.T685P) alteration is located in exon 15 (coding exon 14) of the TRAK2 gene. This alteration results from a A to C substitution at nucleotide position 2053, causing the threonine (T) at amino acid position 685 to be replaced by a proline (P). 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.64
MutPred		0.21		Loss of glycosylation at T685 (P = 0.0453);
MVP		0.27
MPC		0.64
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.66
gMVP		0.75

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: rs1951367334; hg19: chr2-202248850;