Genetic Variant TRAK1:p.Glu638_Glu640dup (chr3-42210085-C-CGGAGGAGGA) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_001265608.2(TRAK1):c.2087_2095dupAGGAGGAGG(p.Glu696_Glu698dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0030 ( 1 hom. )

Consequence

TRAK1
NM_001265608.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.622

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001265608.2

BS2

High AC in GnomAd4 at 560 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAK1	NM_001042646.3 link	c.1963+124_1963+132dupAGGAGGAGG		intron_variant	Intron 14 of 15	ENST00000327628.10	NP_001036111.1	Q9UPV9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAK1	ENST00000327628.10 link	c.1963+124_1963+132dupAGGAGGAGG		intron_variant	Intron 14 of 15	1	NM_001042646.3	ENSP00000328998.5		Q9UPV9-1

Frequencies

GnomAD3 genomes

AF:

0.00381

AC:

561

AN:

147404

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00190

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00629

Gnomad ASJ

AF:

0.0123

Gnomad EAS

AF:

0.0164

Gnomad SAS

AF:

0.00350

Gnomad FIN

AF:

0.00477

Gnomad MID

AF:

0.00649

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.00351

GnomAD2 exomes

AF:

0.00415

AC:

787

AN:

189446

AF XY:

0.00384

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00635

Gnomad ASJ exome

AF:

0.00823

Gnomad EAS exome

AF:

0.0162

Gnomad FIN exome

AF:

0.00315

Gnomad NFE exome

AF:

0.00208

Gnomad OTH exome

AF:

0.00400

GnomAD4 exome

AF:

0.00302

AC:

4322

AN:

1429572

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

2147

AN XY:

710000

show subpopulations

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

African (AFR)

AF:

0.00210

AC:

AN:

32856

American (AMR)

AF:

0.00558

AC:

240

AN:

43046

Ashkenazi Jewish (ASJ)

AF:

0.00897

AC:

222

AN:

24740

East Asian (EAS)

AF:

0.0138

AC:

539

AN:

38934

South Asian (SAS)

AF:

0.00426

AC:

351

AN:

82450

European-Finnish (FIN)

AF:

0.00413

AC:

210

AN:

50798

Middle Eastern (MID)

AF:

0.00525

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.00219

AC:

2389

AN:

1092104

Other (OTH)

AF:

0.00462

AC:

273

AN:

59116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

229

457

686

914

1143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00380

AC:

560

AN:

147496

Hom.:

Cov.:

AF XY:

0.00376

AC XY:

269

AN XY:

71612

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

40072

American (AMR)

AF:

0.00628

AC:

AN:

14802

Ashkenazi Jewish (ASJ)

AF:

0.0123

AC:

AN:

3418

East Asian (EAS)

AF:

0.0164

AC:

AN:

4812

South Asian (SAS)

AF:

0.00350

AC:

AN:

4566

European-Finnish (FIN)

AF:

0.00477

AC:

AN:

9846

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00298

AC:

199

AN:

66788

Other (OTH)

AF:

0.00347

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00426

Hom.:

317

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.62

Mutation Taster

=88/12

polymorphism

(source)

Splicing

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

Publications

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chr3-42210085-C-CGGAGGAGGA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over