2-55240079-C-T

Position:

• chr2-55240079-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000263629.9(MTIF2):​c.1802G>A​(p.Arg601His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R601C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MTIF2 ENST00000263629.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0750

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043563396).
• BP6: Variant 2-55240079-C-T is Benign according to our data. Variant chr2-55240079-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3215520.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTIF2	NM_002453.3	c.1802G>A	p.Arg601His	missense_variant	14/16	ENST00000263629.9	NP_002444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTIF2	ENST00000263629.9	c.1802G>A	p.Arg601His	missense_variant	14/16	1	NM_002453.3	ENSP00000263629.4
MTIF2	ENST00000394600.7	c.1802G>A	p.Arg601His	missense_variant	11/13	2		ENSP00000378099.3
MTIF2	ENST00000403721.5	c.1802G>A	p.Arg601His	missense_variant	13/15	5		ENSP00000384481.1
MTIF2	ENST00000418823.4	c.833G>A	p.Arg278His	missense_variant	6/6	5		ENSP00000403492.4

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251392 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135874

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461458 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 727048

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74484

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000749 Hom.: 0

Bravo AF: 0.000234

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.045	N
LIST_S2	Uncertain	0.88	.;.;D
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.16	N;N;N
MutationTaster	Benign	0.52	D;D;D
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.027
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.18
MVP		0.32
MPC		0.067
ClinPred		0.045	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs186600074; hg19: chr2-55467215;