chr2-176330642-CG-C

Variant names:

• chr2-176330642-CG-C
• rs1575062987
• NM_006554.5:c.603delG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_006554.5(MTX2):​c.603delG​(p.Tyr202IlefsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTX2 NM_006554.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -2.09

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.239 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-176330642-CG-C is Pathogenic according to our data. Variant chr2-176330642-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 805940.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.603delG	p.Tyr202IlefsTer26	frameshift_variant	Exon 9 of 10	ENST00000249442.11	NP_006545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTX2	ENST00000249442.11	c.603delG	p.Tyr202IlefsTer26	frameshift_variant	Exon 9 of 10	1	NM_006554.5	ENSP00000249442.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Progeroid mandibuloacral dysplasia Pathogenic:1

May 12, 2019

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1575062987; hg19: chr2-177195370;