chr2-201380790-T-A

Position:

• chr2-201380790-T-A

Variant summary

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

The NM_015049.3(TRAK2):​c.2498A>T​(p.Asn833Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRAK2 NM_015049.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

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.2498A>T	p.Asn833Ile	missense_variant	16/16	ENST00000332624.8
TRAK2	XM_047445578.1	c.2498A>T	p.Asn833Ile	missense_variant	16/16
TRAK2	XM_047445579.1	c.1865A>T	p.Asn622Ile	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAK2	ENST00000332624.8	c.2498A>T	p.Asn833Ile	missense_variant	16/16	1	NM_015049.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Aug 22, 2023

The c.2498A>T (p.N833I) alteration is located in exon 16 (coding exon 15) of the TRAK2 gene. This alteration results from a A to T substitution at nucleotide position 2498, causing the asparagine (N) at amino acid position 833 to be replaced by an isoleucine (I). 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	0.38
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.42		Loss of disorder (P = 0.0278);
MVP		0.31
MPC		0.61
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.58
gMVP		0.54

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: rs1951334630; hg19: chr2-202245513;