Genetic Variant ENST00000341421.7:c.1904_1921dupAGGAGGAGGAGGAGGAGG (chr3-42210085-C-CGGAGGAGGAGGAGGAGGA) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

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

The ENST00000341421.7(TRAK1):c.1904_1921dupAGGAGGAGGAGGAGGAGG(p.Glu635_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: 0.0000035 ( 0 hom. )

Consequence

TRAK1
ENST00000341421.7 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.622

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TRAK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP3

Nonframeshift variant in repetitive region in ENST00000341421.7

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAK1	NM_001042646.3 link	c.1963+115_1963+132dupAGGAGGAGGAGGAGGAGG		intron_variant	Intron 14 of 15	ENST00000327628.10	NP_001036111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAK1	ENST00000327628.10 link	c.1963+115_1963+132dupAGGAGGAGGAGGAGGAGG		intron_variant	Intron 14 of 15	1	NM_001042646.3	ENSP00000328998.5

Frequencies

GnomAD3 genomes

AF:

0.00000678

AC:

AN:

147430

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000207

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000350

AC:

AN:

1429920

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710168

show subpopulations

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

African (AFR)

AF:

0.0000304

AC:

AN:

32862

American (AMR)

AF:

0.00

AC:

AN:

43078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24744

East Asian (EAS)

AF:

0.00

AC:

AN:

38968

South Asian (SAS)

AF:

0.00

AC:

AN:

82464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5536

European-Non Finnish (NFE)

AF:

0.00000275

AC:

AN:

1092336

Other (OTH)

AF:

0.0000169

AC:

AN:

59126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0135627), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000678

AC:

AN:

147522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71628

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

40080

American (AMR)

AF:

0.00

AC:

AN:

14804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.000208

AC:

AN:

4816

South Asian (SAS)

AF:

0.00

AC:

AN:

4568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66790

Other (OTH)

AF:

0.00

AC:

AN:

2018

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over