3-42210085-CGGAGGAGGAGGAGGA-CGGAGGAGGA

Variant names:

• chr3-42210085-CGGAGGA-C
• rs10634555
• ENST00000341421.7:c.1916_1921delAGGAGG

Variant summary

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

The ENST00000341421.7(TRAK1):​c.1916_1921delAGGAGG​(p.Glu639_Glu640del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000803 in 1,539,126 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: TRAK1 ENST00000341421.7 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• 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+127_1963+132delAGGAGG		intron	N/A	NP_001036111.1
	TRAK1	NM_001265608.2		c.2090_2095delAGGAGG	p.Glu697_Glu698del	disruptive_inframe_deletion	Exon 14 of 14	NP_001252537.1
	TRAK1	NM_014965.5		c.1916_1921delAGGAGG	p.Glu639_Glu640del	disruptive_inframe_deletion	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.1916_1921delAGGAGG	p.Glu639_Glu640del	disruptive_inframe_deletion	Exon 13 of 13	ENSP00000340702.3
	TRAK1	ENST00000327628.10	TSL:1 MANE Select	c.1963+127_1963+132delAGGAGG		intron	N/A	ENSP00000328998.5
	TRAK1	ENST00000613405.4	TSL:2	c.1868_1873delAGGAGG	p.Glu623_Glu624del	disruptive_inframe_deletion	Exon 13 of 13	ENSP00000483516.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 33 AN: 147388 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000751

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000879

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000437

Gnomad FIN AF: 0.000204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000195

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00282 AC: 535 AN: 189446 AF XY: 0.00324

Gnomad AFR exome AF: 0.000691

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.00483

Gnomad EAS exome AF: 0.000411

Gnomad FIN exome AF: 0.00285

Gnomad NFE exome AF: 0.00335

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.000864 AC: 1203 AN: 1391646 Hom.: 0 AF XY: 0.000991 AC XY: 685 AN XY: 691044

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

African (AFR) AF: 0.000499 AC: 16 AN: 32050

American (AMR) AF: 0.000959 AC: 41 AN: 42760

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 39 AN: 24180

East Asian (EAS) AF: 0.0000770 AC: 3 AN: 38936

South Asian (SAS) AF: 0.00226 AC: 182 AN: 80416

European-Finnish (FIN) AF: 0.00105 AC: 52 AN: 49344

Middle Eastern (MID) AF: 0.000919 AC: 5 AN: 5442

European-Non Finnish (NFE) AF: 0.000768 AC: 815 AN: 1060796

Other (OTH) AF: 0.000866 AC: 50 AN: 57722

⚠️ 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: 147480 Hom.: 0 Cov.: 0 AF XY: 0.000321 AC XY: 23 AN XY: 71610

African (AFR) AF: 0.0000749 AC: 3 AN: 40078

American (AMR) AF: 0.000878 AC: 13 AN: 14800

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4816

South Asian (SAS) AF: 0.000438 AC: 2 AN: 4568

European-Finnish (FIN) AF: 0.000204 AC: 2 AN: 9826

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

European-Non Finnish (NFE) AF: 0.000195 AC: 13 AN: 66778

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

Alfa AF: 0.0111 Hom.: 317

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=193/7	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;