Genetic Variant TRAM2:p.Thr334Ile (chr6-52504629-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012288.4(TRAM2):c.1001C>T(p.Thr334Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

TRAM2
NM_012288.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.10

Publications

2 publications found

Variant links:

Genes affected

TRAM2 (HGNC:16855): (translocation associated membrane protein 2) TRAM2 is a component of the translocon, a gated macromolecular channel that controls the posttranslational processing of nascent secretory and membrane proteins at the endoplasmic reticulum (ER) membrane.[supplied by OMIM, Jul 2004]

TRAM2 links:

EFHC1 (HGNC:16406): (EF-hand domain containing 1) This gene encodes an EF-hand-containing calcium binding protein. The encoded protein likely plays a role in calcium homeostasis. Mutations in this gene have been associated with susceptibility to juvenile myoclonic epilepsy and juvenile absence epilepsy. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

EFHC1 Gene-Disease associations (from GenCC):

juvenile myoclonic epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

EFHC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031768143).

BS2

High AC in GnomAd4 at 28 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012288.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAM2	NM_012288.4	MANE Select	c.1001C>T	p.Thr334Ile	missense	Exon 10 of 11	NP_036420.1	Q15035

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRAM2	ENST00000182527.4	TSL:1 MANE Select	c.1001C>T	p.Thr334Ile	missense	Exon 10 of 11	ENSP00000182527.3	Q15035
TRAM2	ENST00000956692.1		c.1100C>T	p.Thr367Ile	missense	Exon 10 of 11	ENSP00000626751.1
TRAM2	ENST00000956690.1		c.1004C>T	p.Thr335Ile	missense	Exon 10 of 11	ENSP00000626749.1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000250

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000227

AC:

AN:

251288

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000301

AC:

440

AN:

1461770

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

207

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.000492

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000362

AC:

402

AN:

1112010

Other (OTH)

AF:

0.000215

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000184

AC:

AN:

152382

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74522

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41594

American (AMR)

AF:

0.000196

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68032

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000338

Hom.:

Bravo

AF:

0.000246

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.077

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.68

M_CAP

Benign

0.0044

MetaRNN

Benign

0.032

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

1.1

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.42

REVEL

Benign

0.045

Sift

Benign

0.19

Sift4G

Benign

0.19

Polyphen

0.0040

Vest4

0.23

MVP

0.043

MPC

0.57

ClinPred

0.014

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.63

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over