chr6-52503253-C-T

Variant names:

• chr6-52503253-C-T
• NM_012288.4:c.1057G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012288.4(TRAM2):​c.1057G>A​(p.Val353Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRAM2 NM_012288.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15354812).

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.1057G>A	p.Val353Met	missense	Exon 11 of 11	NP_036420.1	Q15035

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAM2	ENST00000182527.4	TSL:1 MANE Select	c.1057G>A	p.Val353Met	missense	Exon 11 of 11	ENSP00000182527.3	Q15035
	TRAM2	ENST00000956692.1		c.1156G>A	p.Val386Met	missense	Exon 11 of 11	ENSP00000626751.1
	TRAM2	ENST00000956690.1		c.1060G>A	p.Val354Met	missense	Exon 11 of 11	ENSP00000626749.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	0.085
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.11
Sift	Benign	0.089	T
Sift4G	Uncertain	0.016	D
Polyphen		0.28	B
Vest4		0.18
MutPred		0.30		Gain of MoRF binding (P = 0.0789)
MVP		0.068
MPC		0.53
ClinPred		0.59	D
GERP RS		5.1
Varity_R		0.12
gMVP		0.27
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr6-52368051;