chr6-52504705-G-A

Variant names:

• chr6-52504705-G-A
• rs757947724
• NM_012288.4:c.925C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_012288.4(TRAM2):​c.925C>T​(p.Arg309Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,459,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TRAM2 NM_012288.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.04

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM2	NM_012288.4	c.925C>T	p.Arg309Cys	missense_variant	Exon 10 of 11	ENST00000182527.4	NP_036420.1
TRAM2	XM_011515005.3	c.814C>T	p.Arg272Cys	missense_variant	Exon 9 of 10		XP_011513307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM2	ENST00000182527.4	c.925C>T	p.Arg309Cys	missense_variant	Exon 10 of 11	1	NM_012288.4	ENSP00000182527.3
EFHC1	ENST00000637353.1	c.1851+14355G>A		intron_variant	Intron 10 of 10	5		ENSP00000490441.1
EFHC1	ENST00000636343.1	c.1516-11190G>A		intron_variant	Intron 8 of 8	5		ENSP00000490193.1
EFHC1	ENST00000637602.1	n.*1552+14355G>A		intron_variant	Intron 10 of 10	2		ENSP00000490074.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000810 AC: 2 AN: 246966 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000952

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459490 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725872

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.925C>T (p.R309C) alteration is located in exon 10 (coding exon 10) of the TRAM2 gene. This alteration results from a C to T substitution at nucleotide position 925, causing the arginine (R) at amino acid position 309 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.083	D
MutationAssessor	Benign	1.9	M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.61
Sift	Benign	0.081	T
Sift4G	Benign	0.082	T
Polyphen		1.0	D
Vest4		0.59
MutPred		0.59		Loss of MoRF binding (P = 0.0042);
MVP		0.29
MPC		1.6
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs757947724; hg19: chr6-52369503;