2-176330613-A-T

Variant names:

• chr2-176330613-A-T
• rs74492834
• NM_006554.5:c.573A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006554.5(MTX2):​c.573A>T​(p.Gln191His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,444,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. Q191Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MTX2 NM_006554.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.905
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16554669).

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.573A>T	p.Gln191His	missense	Exon 9 of 10	NP_006545.1	O75431-1
	MTX2	NM_001006635.3		c.543A>T	p.Gln181His	missense	Exon 10 of 11	NP_001006636.1	O75431-2
	MTX2	NM_001319097.2		c.504A>T	p.Gln168His	missense	Exon 9 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.573A>T	p.Gln191His	missense	Exon 9 of 10	ENSP00000249442.6	O75431-1
	MTX2	ENST00000420864.5	TSL:1	n.*663A>T		non_coding_transcript_exon	Exon 10 of 11	ENSP00000403545.1	F8WCW1
	MTX2	ENST00000420864.5	TSL:1	n.*663A>T		3_prime_UTR	Exon 10 of 11	ENSP00000403545.1	F8WCW1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1444050 Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 2 AN XY: 718406

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000302 AC: 1 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 44394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25590

East Asian (EAS) AF: 0.00 AC: 0 AN: 39460

South Asian (SAS) AF: 0.00 AC: 0 AN: 83618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1100294

Other (OTH) AF: 0.00 AC: 0 AN: 59300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000437044), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.91
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.044
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.41
MutPred		0.41		Gain of catalytic residue at Q191 (P = 0.024)
MVP		0.31
MPC		0.16
ClinPred		0.60	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.48
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs74492834; hg19: chr2-177195341;