2-201389798-T-C

Position:

• chr2-201389798-T-C

Variant summary

Our verdict is Benign. Variant got -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 donor 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. 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_donor_region, intron
• Scores: Splicing: ADA: 0.01008
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.652

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAK2	NM_015049.3	c.1193+3A>G		splice_donor_region_variant, intron_variant		ENST00000332624.8
TRAK2	XM_047445578.1	c.1193+3A>G		splice_donor_region_variant, intron_variant
TRAK2	XM_047445579.1	c.560+3A>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAK2	ENST00000332624.8	c.1193+3A>G		splice_donor_region_variant, intron_variant		1	NM_015049.3	P1
STRADB	ENST00000458269.6	c.28+1723T>C		intron_variant		5

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

GnomAD3 exomes AF: 0.00805 AC: 2002 AN: 248772 Hom.: 10 AF XY: 0.00788 AC XY: 1060 AN XY: 134440

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 SAS exome AF: 0.000670

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

Gnomad4 AFR exome AF: 0.00178

Gnomad4 AMR exome AF: 0.00343

Gnomad4 ASJ exome AF: 0.000269

Gnomad4 EAS exome AF: 0.00182

Gnomad4 SAS exome AF: 0.000748

Gnomad4 FIN exome AF: 0.00589

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0103

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

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0127 Hom.: 9

Bravo AF: 0.00839

Asia WGS AF: 0.00116 AC: 4 AN: 3474

EpiCase AF: 0.0118

EpiControl AF: 0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs41271463; hg19: chr2-202254521;