chr2-201395433-C-A

Variant names:

• chr2-201395433-C-A
• rs1295319552
• NM_015049.3:c.781G>T

Variant summary

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

The NM_015049.3(TRAK2):​c.781G>T​(p.Ala261Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000723 in 1,382,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TRAK2 NM_015049.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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=0.07853815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAK2	NM_015049.3	c.781G>T	p.Ala261Ser	missense_variant	Exon 8 of 16	ENST00000332624.8	NP_055864.2
TRAK2	XM_047445578.1	c.781G>T	p.Ala261Ser	missense_variant	Exon 8 of 16		XP_047301534.1
TRAK2	XM_047445579.1	c.148G>T	p.Ala50Ser	missense_variant	Exon 5 of 13		XP_047301535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAK2	ENST00000332624.8	c.781G>T	p.Ala261Ser	missense_variant	Exon 8 of 16	1	NM_015049.3	ENSP00000328875.3
TRAK2	ENST00000430254.1	c.781G>T	p.Ala261Ser	missense_variant	Exon 8 of 8	2		ENSP00000409333.1
STRADB	ENST00000458269.6	c.28+7358C>A		intron_variant	Intron 1 of 5	5		ENSP00000409552.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1382694 Hom.: 0 Cov.: 33 AF XY: 0.00000147 AC XY: 1 AN XY: 680674

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.42e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.781G>T (p.A261S) alteration is located in exon 8 (coding exon 7) of the TRAK2 gene. This alteration results from a G to T substitution at nucleotide position 781, causing the alanine (A) at amino acid position 261 to be replaced by a serine (S). 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	0.094
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0077	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.12
Sift	Benign	0.58	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.69	P;.
Vest4		0.079
MutPred		0.34		Gain of phosphorylation at A261 (P = 0.0605);Gain of phosphorylation at A261 (P = 0.0605);
MVP		0.085
MPC		0.13
ClinPred		0.77	D
GERP RS		5.8
Varity_R		0.072
gMVP		0.11

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: rs1295319552; hg19: chr2-202260156;