chr6-52504629-G-T

Variant names:

• chr6-52504629-G-T
• rs199535862
• NM_012288.4:c.1001C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012288.4(TRAM2):​c.1001C>A​(p.Thr334Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,770 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T334I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRAM2 NM_012288.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031498015).

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>A	p.Thr334Lys	missense	Exon 10 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.1001C>A	p.Thr334Lys	missense	Exon 10 of 11	ENSP00000182527.3	Q15035
	TRAM2	ENST00000956692.1		c.1100C>A	p.Thr367Lys	missense	Exon 10 of 11	ENSP00000626751.1
	TRAM2	ENST00000956690.1		c.1004C>A	p.Thr335Lys	missense	Exon 10 of 11	ENSP00000626749.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.65
DEOGEN2	Benign	0.054	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.35		Loss of phosphorylation at T334 (P = 0.0036)
MVP		0.043
MPC		0.64
ClinPred		0.027	T
GERP RS		2.8
Varity_R		0.022
gMVP		0.70
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs199535862; hg19: chr6-52369427;