NM_006554.5:c.2T>A

Variant names:

• chr2-176269631-T-A
• rs1392596720
• NM_006554.5:c.2T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Supporting PM2 PP5

The NM_006554.5(MTX2):​c.2T>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTX2 NM_006554.5 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 3.85

Genes affected

MTX2 (HGNC:7506): (metaxin 2) The protein encoded by this gene is highly similar to the metaxin 2 protein from mouse, which has been shown to interact with the mitochondrial membrane protein metaxin 1. Because of this similarity, it is thought that the encoded protein is peripherally associated with the cytosolic face of the outer mitochondrial membrane, and that it is involved in the import of proteins into the mitochondrion. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 7. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 50 codons. Genomic position: 176323404. Lost 0.187 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-176269631-T-A is Pathogenic according to our data. Variant chr2-176269631-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 805937.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTX2	NM_006554.5	c.2T>A	p.Met1?	start_lost	Exon 1 of 10	ENST00000249442.11	NP_006545.1
MTX2	NM_001319097.2	c.2T>A	p.Met1?	start_lost	Exon 1 of 10		NP_001306026.1
MTX2	NM_001319098.2	c.2T>A	p.Met1?	start_lost	Exon 1 of 9		NP_001306027.1
MTX2	NM_001006635.3	c.-233T>A		5_prime_UTR_variant	Exon 1 of 11		NP_001006636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTX2	ENST00000249442.11	c.2T>A	p.Met1?	start_lost	Exon 1 of 10	1	NM_006554.5	ENSP00000249442.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Progeroid mandibuloacral dysplasia Pathogenic:1

Feb 01, 2017

Marseille Medical Genetics, U1251, Aix Marseille University, Inserm

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mandibuloacral dysplasia progeroid syndrome Pathogenic:1

Dec 16, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.026	T;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.91	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.95	P;.;.
Vest4		0.92
MutPred		0.89		Loss of stability (P = 0.0187);Loss of stability (P = 0.0187);Loss of stability (P = 0.0187);
MVP		0.53
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs1392596720; hg19: chr2-177134359;