chr3-42210085-C-CGGAGGAGGAGGA

Variant names:

• chr3-42210085-C-CGGAGGAGGAGGA
• rs10634555
• ENST00000341421.7:c.1910_1921dupAGGAGGAGGAGG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The ENST00000341421.7(TRAK1):​c.1910_1921dupAGGAGGAGGAGG​(p.Glu637_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00016 (0 hom.)
  • Failed GnomAD Quality Control
• 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 -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000341421.7
• BS2: High AC in GnomAd4 at 33 AD gene.

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+121_1963+132dupAGGAGGAGGAGG		intron	N/A	NP_001036111.1
	TRAK1	NM_001265608.2		c.2084_2095dupAGGAGGAGGAGG	p.Glu695_Glu698dup	disruptive_inframe_insertion	Exon 14 of 14	NP_001252537.1
	TRAK1	NM_014965.5		c.1910_1921dupAGGAGGAGGAGG	p.Glu637_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.1910_1921dupAGGAGGAGGAGG	p.Glu637_Glu640dup	disruptive_inframe_insertion	Exon 13 of 13	ENSP00000340702.3
	TRAK1	ENST00000327628.10	TSL:1 MANE Select	c.1963+121_1963+132dupAGGAGGAGGAGG		intron	N/A	ENSP00000328998.5
	TRAK1	ENST00000613405.4	TSL:2	c.1862_1873dupAGGAGGAGGAGG	p.Glu621_Glu624dup	disruptive_inframe_insertion	Exon 13 of 13	ENSP00000483516.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 33 AN: 147426 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000270

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00104

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000254

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000160 AC: 229 AN: 1429888 Hom.: 0 Cov.: 0 AF XY: 0.000162 AC XY: 115 AN XY: 710146

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

African (AFR) AF: 0.000457 AC: 15 AN: 32858

American (AMR) AF: 0.000325 AC: 14 AN: 43078

Ashkenazi Jewish (ASJ) AF: 0.0000404 AC: 1 AN: 24744

East Asian (EAS) AF: 0.000205 AC: 8 AN: 38968

South Asian (SAS) AF: 0.000109 AC: 9 AN: 82462

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

Middle Eastern (MID) AF: 0.000361 AC: 2 AN: 5534

European-Non Finnish (NFE) AF: 0.000153 AC: 167 AN: 1092314

Other (OTH) AF: 0.000220 AC: 13 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: 0.000224 AC: 33 AN: 147518 Hom.: 1 Cov.: 0 AF XY: 0.000168 AC XY: 12 AN XY: 71626

African (AFR) AF: 0.000150 AC: 6 AN: 40078

American (AMR) AF: 0.000270 AC: 4 AN: 14804

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

East Asian (EAS) AF: 0.00104 AC: 5 AN: 4816

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4568

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000255 AC: 17 AN: 66788

Other (OTH) AF: 0.00 AC: 0 AN: 2018

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;