chr3-42091512-C-CCTCTGCCAGGA

Variant names:

• chr3-42091512-C-CCTCTGCCAGGA
• NM_001042646.3:c.52_62dupGGACTCTGCCA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_001042646.3(TRAK1):​c.52_62dupGGACTCTGCCA​(p.His21GlnfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRAK1 NM_001042646.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.476
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.978 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 3-42091512-C-CCTCTGCCAGGA is Pathogenic according to our data. Variant chr3-42091512-C-CCTCTGCCAGGA is described in ClinVar as Pathogenic. ClinVar VariationId is 3721550.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042646.3. 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
	TRAK1	NM_001042646.3	MANE Select	c.52_62dupGGACTCTGCCA	p.His21GlnfsTer40	frameshift	Exon 1 of 16	NP_001036111.1	Q9UPV9-1
	TRAK1	NM_001349246.2		c.52_62dupGGACTCTGCCA	p.His21GlnfsTer40	frameshift	Exon 1 of 16	NP_001336175.1
	TRAK1	NM_001265608.2		c.52_62dupGGACTCTGCCA	p.His21GlnfsTer40	frameshift	Exon 1 of 14	NP_001252537.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAK1	ENST00000327628.10	TSL:1 MANE Select	c.52_62dupGGACTCTGCCA	p.His21GlnfsTer40	frameshift	Exon 1 of 16	ENSP00000328998.5	Q9UPV9-1
	TRAK1	ENST00000673621.3		c.175+4121_175+4131dupGGACTCTGCCA		intron	N/A	ENSP00000500819.2	A0A5F9ZI06
	TRAK1	ENST00000487159.5	TSL:5	c.-222+4121_-222+4131dupGGACTCTGCCA		intron	N/A	ENSP00000486713.1	A0A0D9SFL5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.48

Splicing

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

Other links and lift over

hg19: chr3-42133004;