chr2-176328352-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_006554.5(MTX2):c.345G>A(p.Met115Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000063 in 1,587,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

MTX2
NM_006554.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Publications

0 publications found

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 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

MTX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000626 (9/1436924) while in subpopulation EAS AF = 0.00013 (5/38604). AF 95% confidence interval is 0.0000502. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTX2	NM_006554.5	MANE Select	c.345G>A	p.Met115Ile	missense	Exon 6 of 10	NP_006545.1	O75431-1
MTX2	NM_001006635.3		c.315G>A	p.Met105Ile	missense	Exon 7 of 11	NP_001006636.1	O75431-2
MTX2	NM_001319097.2		c.345G>A	p.Met115Ile	missense	Exon 6 of 10	NP_001306026.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTX2	ENST00000249442.11	TSL:1 MANE Select	c.345G>A	p.Met115Ile	missense	Exon 6 of 10	ENSP00000249442.6	O75431-1
MTX2	ENST00000420864.5	TSL:1	n.*435G>A		non_coding_transcript_exon	Exon 7 of 11	ENSP00000403545.1	F8WCW1
MTX2	ENST00000420864.5	TSL:1	n.*435G>A		3_prime_UTR	Exon 7 of 11	ENSP00000403545.1	F8WCW1

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000252

AC:

AN:

237984

AF XY:

0.0000232

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000174

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000274

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000626

AC:

AN:

1436924

Hom.:

Cov.:

AF XY:

0.00000699

AC XY:

AN XY:

714948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32334

American (AMR)

AF:

0.00

AC:

AN:

41054

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25436

East Asian (EAS)

AF:

0.000130

AC:

AN:

38604

South Asian (SAS)

AF:

0.00

AC:

AN:

81990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52788

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1100068

Other (OTH)

AF:

0.0000169

AC:

AN:

59020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150930

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73682

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41270

American (AMR)

AF:

0.00

AC:

AN:

15058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67292

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000412

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.068

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.36

Sift

Uncertain

0.023

Sift4G

Benign

0.13

Polyphen

0.041

Vest4

0.87

MutPred

0.59

Loss of ubiquitination at K112 (P = 0.0487)

MVP

0.26

MPC

0.21

ClinPred

0.29

GERP RS

5.9

Varity_R

0.36

gMVP

0.70

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over