chr3-42210085-C-CGGAGGAGGAGGAGGA

Variant names:

• chr3-42210085-C-CGGAGGAGGAGGAGGA
• rs10634555
• ENST00000341421.7:c.1907_1921dupAGGAGGAGGAGGAGG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The ENST00000341421.7(TRAK1):​c.1907_1921dupAGGAGGAGGAGGAGG​(p.Glu636_Glu640dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. 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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TRAK1 ENST00000341421.7 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.622
• Publications: 19 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):

• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000341421.7

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000341421.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAK1	NM_001042646.3	MANE Select	c.1963+118_1963+132dupAGGAGGAGGAGGAGG		intron	N/A	NP_001036111.1
	TRAK1	NM_001265608.2		c.2081_2095dupAGGAGGAGGAGGAGG	p.Glu694_Glu698dup	disruptive_inframe_insertion	Exon 14 of 14	NP_001252537.1
	TRAK1	NM_014965.5		c.1907_1921dupAGGAGGAGGAGGAGG	p.Glu636_Glu640dup	disruptive_inframe_insertion	Exon 13 of 13	NP_055780.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAK1	ENST00000341421.7	TSL:1	c.1907_1921dupAGGAGGAGGAGGAGG	p.Glu636_Glu640dup	disruptive_inframe_insertion	Exon 13 of 13	ENSP00000340702.3
	TRAK1	ENST00000327628.10	TSL:1 MANE Select	c.1963+118_1963+132dupAGGAGGAGGAGGAGG		intron	N/A	ENSP00000328998.5
	TRAK1	ENST00000613405.4	TSL:2	c.1859_1873dupAGGAGGAGGAGGAGG	p.Glu620_Glu624dup	disruptive_inframe_insertion	Exon 13 of 13	ENSP00000483516.1

Frequencies

GnomAD3 genomes AF: 0.00000678 AC: 1 AN: 147430 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 17 AN: 1429906 Hom.: 0 Cov.: 0 AF XY: 0.0000141 AC XY: 10 AN XY: 710158

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32862

American (AMR) AF: 0.00 AC: 0 AN: 43078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24744

East Asian (EAS) AF: 0.000180 AC: 7 AN: 38964

South Asian (SAS) AF: 0.00 AC: 0 AN: 82466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 0.00000915 AC: 10 AN: 1092326

Other (OTH) AF: 0.00 AC: 0 AN: 59124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000678 AC: 1 AN: 147430 Hom.: 0 Cov.: 0 AF XY: 0.0000140 AC XY: 1 AN XY: 71516

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 39972

American (AMR) AF: 0.00 AC: 0 AN: 14788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 4830

South Asian (SAS) AF: 0.00 AC: 0 AN: 4574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66800

Other (OTH) AF: 0.00 AC: 0 AN: 1998

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 317

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=88/12	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs10634555; hg19: chr3-42251577;