rs41271463

Variant names:

• chr2-201389798-T-C
• rs41271463
• NM_015049.3:c.1193+3A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_015049.3(TRAK2):​c.1193+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,609,162 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (17 hom., cov: 32)
  • Exomes 𝑓: 0.012 (141 hom.)
• Consequence: TRAK2 NM_015049.3 splice_region, intron
• Scores: Splicing: ADA: 0.01008
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.652
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-201389798-T-C is Benign according to our data. Variant chr2-201389798-T-C is described in ClinVar as Benign. ClinVar VariationId is 779409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00894 (1362/152324) while in subpopulation NFE AF = 0.0163 (1108/68024). AF 95% confidence interval is 0.0155. There are 17 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015049.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAK2	NM_015049.3	MANE Select	c.1193+3A>G		splice_region intron	N/A	NP_055864.2	O60296-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAK2	ENST00000332624.8	TSL:1 MANE Select	c.1193+3A>G		splice_region intron	N/A	ENSP00000328875.3	O60296-1
	TRAK2	ENST00000861749.1		c.1262+3A>G		splice_region intron	N/A	ENSP00000531808.1
	TRAK2	ENST00000861746.1		c.1193+3A>G		splice_region intron	N/A	ENSP00000531805.1

Frequencies

GnomAD3 genomes AF: 0.00895 AC: 1363 AN: 152206 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00805 AC: 2002 AN: 248772 AF XY: 0.00788

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.000400

Gnomad EAS exome AF: 0.00252

Gnomad FIN exome AF: 0.00519

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0100

GnomAD4 exome AF: 0.0121 AC: 17658 AN: 1456838 Hom.: 141 Cov.: 30 AF XY: 0.0118 AC XY: 8519 AN XY: 724948

African (AFR) AF: 0.00178 AC: 59 AN: 33226

American (AMR) AF: 0.00343 AC: 151 AN: 44078

Ashkenazi Jewish (ASJ) AF: 0.000269 AC: 7 AN: 26054

East Asian (EAS) AF: 0.00182 AC: 72 AN: 39662

South Asian (SAS) AF: 0.000748 AC: 64 AN: 85534

European-Finnish (FIN) AF: 0.00589 AC: 314 AN: 53336

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5750

European-Non Finnish (NFE) AF: 0.0148 AC: 16366 AN: 1108992

Other (OTH) AF: 0.0103 AC: 621 AN: 60206

GnomAD4 genome AF: 0.00894 AC: 1362 AN: 152324 Hom.: 17 Cov.: 32 AF XY: 0.00788 AC XY: 587 AN XY: 74488

African (AFR) AF: 0.00243 AC: 101 AN: 41574

American (AMR) AF: 0.00340 AC: 52 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1108 AN: 68024

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0125 Hom.: 9

Bravo AF: 0.00839

Asia WGS AF: 0.00116 AC: 4 AN: 3474

EpiCase AF: 0.0118

EpiControl AF: 0.0112

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.92
PhyloP100		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41271463; hg19: chr2-202254521;