NM_001042646.3:c.52_62dupGGACTCTGCCA

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 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. 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-42091512-C-CCTCTGCCAGGA is Pathogenic according to our data. Variant chr3-42091512-C-CCTCTGCCAGGA is described in ClinVar as [Pathogenic]. Clinvar id is 3721550.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAK1	NM_001042646.3	c.52_62dupGGACTCTGCCA	p.His21GlnfsTer40	frameshift_variant	Exon 1 of 16	ENST00000327628.10	NP_001036111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAK1	ENST00000327628.10	c.52_62dupGGACTCTGCCA	p.His21GlnfsTer40	frameshift_variant	Exon 1 of 16	1	NM_001042646.3	ENSP00000328998.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.His21Glnfs*40) in the TRAK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRAK1 are known to be pathogenic (PMID: 28364549, 28940097). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TRAK1-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-42133004;