chr2-176328298-TTC-T

Variant names:

• chr2-176328298-TTC-T
• rs768727228
• NM_006554.5:c.295_296delCT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.01
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• mandibuloacral dysplasia progeroid syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• mandibuloacral dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 827676.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006554.5. 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
	MTX2	NM_006554.5	MANE Select	c.295_296delCT	p.Leu99fs	frameshift	Exon 6 of 10	NP_006545.1	O75431-1
	MTX2	NM_001006635.3		c.265_266delCT	p.Leu89fs	frameshift	Exon 7 of 11	NP_001006636.1	O75431-2
	MTX2	NM_001319097.2		c.295_296delCT	p.Leu99fs	frameshift	Exon 6 of 10	NP_001306026.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTX2	ENST00000249442.11	TSL:1 MANE Select	c.295_296delCT	p.Leu99fs	frameshift	Exon 6 of 10	ENSP00000249442.6	O75431-1
	MTX2	ENST00000420864.5	TSL:1	n.*385_*386delCT		non_coding_transcript_exon	Exon 7 of 11	ENSP00000403545.1	F8WCW1
	MTX2	ENST00000420864.5	TSL:1	n.*385_*386delCT		3_prime_UTR	Exon 7 of 11	ENSP00000403545.1	F8WCW1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000458 AC: 1 AN: 218512 AF XY: 0.00000839

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: 0.00000961

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1410568 Hom.: 0 AF XY: 0.00000143 AC XY: 1 AN XY: 701674

African (AFR) AF: 0.00 AC: 0 AN: 30768

American (AMR) AF: 0.00 AC: 0 AN: 34560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24064

East Asian (EAS) AF: 0.00 AC: 0 AN: 38226

South Asian (SAS) AF: 0.00 AC: 0 AN: 76754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5414

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090816

Other (OTH) AF: 0.00 AC: 0 AN: 57746

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	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 (1)
1	-	-	Mandibuloacral dysplasia progeroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=5/195	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs768727228; hg19: chr2-177193026;