Genetic Variant NM_006554.5:c.295_296delCT (chr2-176328298-TTC-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_006554.5(MTX2):c.295_296delCT(p.Leu99fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,410,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MTX2
NM_006554.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 8.01

Variant links:

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]

MTX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-176328298-TTC-T is Pathogenic according to our data. Variant chr2-176328298-TTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 827676.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 link	c.295_296delCT	p.Leu99fs	frameshift_variant	Exon 6 of 10	ENST00000249442.11	NP_006545.1	O75431-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTX2	ENST00000249442.11 link	c.295_296delCT	p.Leu99fs	frameshift_variant	Exon 6 of 10	1	NM_006554.5	ENSP00000249442.6		O75431-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000458

AC:

AN:

218512

Hom.:

AF XY:

0.00000839

AC XY:

AN XY:

119228

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000961

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1410568

Hom.:

AF XY:

0.00000143

AC XY:

AN XY:

701674

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hypertensive disorder;C0025990:Micrognathia;C0040433:Dental crowding;C1260926:Abnormality of skin pigmentation;C1857710:Progeroid facial appearance;C1859778:Postnatal growth retardation;C4021159:Facial shape deformation;C4025739:Acroosteolysis of distal phalanges (feet);C4025870:Abnormal mandible morphology;C4025901:Abnormality of body height

Pathogenic:1

Dec 15, 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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over