2-55236709-C-T

Position:

• chr2-55236709-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000263629.9(MTIF2):​c.2123G>A​(p.Arg708Lys) 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. 16/21 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: MTIF2 ENST00000263629.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.458

Genes affected

MTIF2 (HGNC:7441): (mitochondrial translational initiation factor 2) During the initiation of protein biosynthesis, initiation factor-2 (IF-2) promotes the binding of the initiator tRNA to the small subunit of the ribosome in a GTP-dependent manner. Prokaryotic IF-2 is a single polypeptide, while eukaryotic cytoplasmic IF-2 (eIF-2) is a trimeric protein. Bovine liver mitochondria contain IF-2(mt), an 85-kD monomeric protein that is equivalent to prokaryotic IF-2. The predicted 727-amino acid human protein contains a 29-amino acid presequence. Human IF-2(mt) shares 32 to 38% amino acid sequence identity with yeast IF-2(mt) and several prokaryotic IF-2s, with the greatest degree of conservation in the G domains of the proteins. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057211995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTIF2	NM_002453.3	c.2123G>A	p.Arg708Lys	missense_variant	16/16	ENST00000263629.9	NP_002444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTIF2	ENST00000263629.9	c.2123G>A	p.Arg708Lys	missense_variant	16/16	1	NM_002453.3	ENSP00000263629.4
MTIF2	ENST00000394600.7	c.2123G>A	p.Arg708Lys	missense_variant	13/13	2		ENSP00000378099.3
MTIF2	ENST00000403721.5	c.2123G>A	p.Arg708Lys	missense_variant	15/15	5		ENSP00000384481.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.2123G>A (p.R708K) alteration is located in exon 17 (coding exon 13) of the MTIF2 gene. This alteration results from a G to A substitution at nucleotide position 2123, causing the arginine (R) at amino acid position 708 to be replaced by a lysine (K). 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	0.063
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.2
DANN	Benign	0.54
DEOGEN2	Benign	0.10	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.65	.;.;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.32	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.56	N;N;N
REVEL	Benign	0.039
Sift	Benign	0.91	T;T;T
Sift4G	Benign	0.93	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.067
MutPred		0.38		Gain of ubiquitination at R708 (P = 0.0192);Gain of ubiquitination at R708 (P = 0.0192);Gain of ubiquitination at R708 (P = 0.0192);
MVP		0.49
MPC		0.056
ClinPred		0.022	T
GERP RS		0.97
Varity_R		0.038
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-55463845;