2-55242964-C-G

Variant names:

• chr2-55242964-C-G
• NM_002453.3:c.1681G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002453.3(MTIF2):​c.1681G>C​(p.Val561Leu) 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 NM_002453.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12208566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTIF2	NM_002453.3	c.1681G>C	p.Val561Leu	missense_variant	Exon 13 of 16	ENST00000263629.9	NP_002444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTIF2	ENST00000263629.9	c.1681G>C	p.Val561Leu	missense_variant	Exon 13 of 16	1	NM_002453.3	ENSP00000263629.4
MTIF2	ENST00000394600.7	c.1681G>C	p.Val561Leu	missense_variant	Exon 10 of 13	2		ENSP00000378099.3
MTIF2	ENST00000403721.5	c.1681G>C	p.Val561Leu	missense_variant	Exon 12 of 15	5		ENSP00000384481.1
MTIF2	ENST00000418823.4	c.712G>C	p.Val238Leu	missense_variant	Exon 5 of 6	5		ENSP00000403492.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1681G>C (p.V561L) alteration is located in exon 14 (coding exon 10) of the MTIF2 gene. This alteration results from a G to C substitution at nucleotide position 1681, causing the valine (V) at amino acid position 561 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.47
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;.;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.41	N;N;N
REVEL	Benign	0.039
Sift	Benign	0.92	T;T;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.16
MutPred		0.49		Loss of catalytic residue at V561 (P = 0.0079);Loss of catalytic residue at V561 (P = 0.0079);Loss of catalytic residue at V561 (P = 0.0079);
MVP		0.55
MPC		0.056
ClinPred		0.17	T
GERP RS		2.7
Varity_R		0.050
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr2-55470100;