Genetic Variant MTX2:p.Lys237Asn (chr2-176337583-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006554.5(MTX2):c.711A>C(p.Lys237Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

MTX2
NM_006554.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.88

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:

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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;

BP4

Computational evidence support a benign effect (MetaRNN=0.28798962).

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.711A>C	p.Lys237Asn	missense	Exon 10 of 10	NP_006545.1	O75431-1
MTX2	NM_001006635.3		c.681A>C	p.Lys227Asn	missense	Exon 11 of 11	NP_001006636.1	O75431-2
MTX2	NM_001319097.2		c.642A>C	p.Lys214Asn	missense	Exon 10 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.711A>C	p.Lys237Asn	missense	Exon 10 of 10	ENSP00000249442.6	O75431-1
MTX2	ENST00000420864.5	TSL:1	n.*801A>C		non_coding_transcript_exon	Exon 11 of 11	ENSP00000403545.1	F8WCW1
MTX2	ENST00000420864.5	TSL:1	n.*801A>C		3_prime_UTR	Exon 11 of 11	ENSP00000403545.1	F8WCW1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

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

Uncertain

0.49

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

Eigen

Benign

0.071

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.015

MetaRNN

Benign

0.29

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

1.9

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.7

REVEL

Benign

0.098

Sift

Benign

0.17

Sift4G

Benign

0.19

Polyphen

0.34

Vest4

0.48

MutPred

0.41

Loss of ubiquitination at K237 (P = 0.0244)

MVP

0.54

MPC

0.25

ClinPred

0.92

GERP RS

4.8

Varity_R

0.17

gMVP

0.57

Mutation Taster

=51/49

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over