2-55240104-T-G

Variant names:

• chr2-55240104-T-G
• rs199962830
• NM_002453.3:c.1777A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002453.3(MTIF2):​c.1777A>C​(p.Ile593Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. I593V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MTIF2 NM_002453.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17663631).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002453.3. 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
	MTIF2	NM_002453.3	MANE Select	c.1777A>C	p.Ile593Leu	missense	Exon 14 of 16	NP_002444.2
	MTIF2	NM_001005369.1		c.1777A>C	p.Ile593Leu	missense	Exon 15 of 17	NP_001005369.1	P46199
	MTIF2	NM_001321001.1		c.1777A>C	p.Ile593Leu	missense	Exon 14 of 16	NP_001307930.1	P46199

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTIF2	ENST00000263629.9	TSL:1 MANE Select	c.1777A>C	p.Ile593Leu	missense	Exon 14 of 16	ENSP00000263629.4	P46199
	MTIF2	ENST00000956673.1		c.1825A>C	p.Ile609Leu	missense	Exon 16 of 18	ENSP00000626732.1
	MTIF2	ENST00000918027.1		c.1798A>C	p.Ile600Leu	missense	Exon 15 of 17	ENSP00000588086.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251376 AF XY: 0.0000294

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461670 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727152

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0031
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.070
Sift	Benign	0.30	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.32
MutPred		0.55		Loss of sheet (P = 0.0025)
MVP		0.57
MPC		0.057
ClinPred		0.19	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.66
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199962830; hg19: chr2-55467240;