rs61734483

Variant names:

• chr6-52506128-C-A
• NM_012288.4:c.635G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-52506128-C-A
• chr6-52506128-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012288.4(TRAM2):​c.635G>T​(p.Arg212Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R212H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRAM2 NM_012288.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAM2	NM_012288.4	c.635G>T	p.Arg212Leu	missense_variant	Exon 8 of 11	ENST00000182527.4	NP_036420.1
TRAM2	XM_011515005.3	c.524G>T	p.Arg175Leu	missense_variant	Exon 7 of 10		XP_011513307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRAM2	ENST00000182527.4	c.635G>T	p.Arg212Leu	missense_variant	Exon 8 of 11	1	NM_012288.4	ENSP00000182527.3
EFHC1	ENST00000637353.1	c.1851+15778C>A		intron_variant	Intron 10 of 10	5		ENSP00000490441.1
EFHC1	ENST00000636343.1	c.1516-9767C>A		intron_variant	Intron 8 of 8	5		ENSP00000490193.1
EFHC1	ENST00000637602.1	n.*1552+15778C>A		intron_variant	Intron 10 of 10	2		ENSP00000490074.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.82	P
Vest4		0.85
MutPred		0.73		Loss of methylation at R212 (P = 0.083);
MVP		0.80
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-52370926;