3-42125451-C-T

Variant names:

• chr3-42125451-C-T
• rs61742102
• NM_001042646.3:c.123C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001349245.1(TRAK1):​c.-190C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,614,130 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (99 hom.)
• Consequence: TRAK1 NM_001349245.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.701
• Publications: 2 publications found

Genes affected

TRAK1 (HGNC:29947): (trafficking kinesin protein 1) Predicted to enable GABA receptor binding activity and myosin binding activity. Involved in endosome to lysosome transport. Located in early endosome and mitochondrion. Implicated in developmental and epileptic encephalopathy 68. [provided by Alliance of Genome Resources, Apr 2022]

TRAK1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 68

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-42125451-C-T is Benign according to our data. Variant chr3-42125451-C-T is described in ClinVar as Benign. ClinVar VariationId is 1600230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00275 (419/152276) while in subpopulation SAS AF = 0.0383 (185/4824). AF 95% confidence interval is 0.0338. There are 5 homozygotes in GnomAd4. There are 229 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 419 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349245.1. 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
	TRAK1	NM_001042646.3	MANE Select	c.123C>T	p.Val41Val	synonymous	Exon 2 of 16	NP_001036111.1	Q9UPV9-1
	TRAK1	NM_001349245.1		c.-190C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 16	NP_001336174.1
	TRAK1	NM_001349246.2		c.123C>T	p.Val41Val	synonymous	Exon 2 of 16	NP_001336175.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAK1	ENST00000327628.10	TSL:1 MANE Select	c.123C>T	p.Val41Val	synonymous	Exon 2 of 16	ENSP00000328998.5	Q9UPV9-1
	TRAK1	ENST00000487159.5	TSL:5	c.-190C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 17	ENSP00000486713.1	A0A0D9SFL5
	TRAK1	ENST00000672026.1		c.-190C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 18	ENSP00000500099.1	A0A5F9ZH95

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 419 AN: 152156 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00624 AC: 1557 AN: 249354 AF XY: 0.00799

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00646

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00810

GnomAD4 exome AF: 0.00375 AC: 5488 AN: 1461854 Hom.: 99 Cov.: 31 AF XY: 0.00492 AC XY: 3578 AN XY: 727232

African (AFR) AF: 0.00260 AC: 87 AN: 33480

American (AMR) AF: 0.00161 AC: 72 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 138 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0388 AC: 3347 AN: 86240

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.0248 AC: 143 AN: 5768

European-Non Finnish (NFE) AF: 0.00124 AC: 1382 AN: 1112000

Other (OTH) AF: 0.00518 AC: 313 AN: 60396

GnomAD4 genome AF: 0.00275 AC: 419 AN: 152276 Hom.: 5 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74456

African (AFR) AF: 0.00140 AC: 58 AN: 41566

American (AMR) AF: 0.00235 AC: 36 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0383 AC: 185 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00174 AC: 118 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.00213

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

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	-0.58
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs61742102; hg19: chr3-42166943;