chr2-176330613-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_006554.5(MTX2):​c.573A>G​(p.Gln191Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00918 in 1,594,952 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (92 hom.)
• Consequence: MTX2 NM_006554.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-176330613-A-G is Benign according to our data. Variant chr2-176330613-A-G is described in ClinVar as Benign. ClinVar VariationId is 2651565.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.905 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0068 (1027/151136) while in subpopulation NFE AF = 0.0105 (704/67266). AF 95% confidence interval is 0.00983. There are 5 homozygotes in GnomAd4. There are 481 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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>G	p.Gln191Gln	synonymous	Exon 9 of 10	NP_006545.1	O75431-1
	MTX2	NM_001006635.3		c.543A>G	p.Gln181Gln	synonymous	Exon 10 of 11	NP_001006636.1	O75431-2
	MTX2	NM_001319097.2		c.504A>G	p.Gln168Gln	synonymous	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>G	p.Gln191Gln	synonymous	Exon 9 of 10	ENSP00000249442.6	O75431-1
	MTX2	ENST00000420864.5	TSL:1	n.*663A>G		non_coding_transcript_exon	Exon 10 of 11	ENSP00000403545.1	F8WCW1
	MTX2	ENST00000420864.5	TSL:1	n.*663A>G		3_prime_UTR	Exon 10 of 11	ENSP00000403545.1	F8WCW1

Frequencies

GnomAD3 genomes AF: 0.00677 AC: 1022 AN: 151018 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00358

Gnomad ASJ AF: 0.00725

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00435

GnomAD2 exomes AF: 0.00676 AC: 1681 AN: 248588 AF XY: 0.00667

Gnomad AFR exome AF: 0.00286

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00523

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00645

GnomAD4 exome AF: 0.00943 AC: 13622 AN: 1443816 Hom.: 92 Cov.: 29 AF XY: 0.00929 AC XY: 6673 AN XY: 718292

African (AFR) AF: 0.00251 AC: 83 AN: 33108

American (AMR) AF: 0.00270 AC: 120 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00543 AC: 139 AN: 25590

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

South Asian (SAS) AF: 0.00213 AC: 178 AN: 83610

European-Finnish (FIN) AF: 0.0135 AC: 710 AN: 52702

Middle Eastern (MID) AF: 0.000897 AC: 5 AN: 5574

European-Non Finnish (NFE) AF: 0.0109 AC: 11966 AN: 1100092

Other (OTH) AF: 0.00710 AC: 421 AN: 59290

GnomAD4 genome AF: 0.00680 AC: 1027 AN: 151136 Hom.: 5 Cov.: 32 AF XY: 0.00651 AC XY: 481 AN XY: 73874

African (AFR) AF: 0.00253 AC: 105 AN: 41462

American (AMR) AF: 0.00357 AC: 54 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.00725 AC: 25 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4814

European-Finnish (FIN) AF: 0.0115 AC: 121 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 704 AN: 67266

Other (OTH) AF: 0.00431 AC: 9 AN: 2090

Alfa AF: 0.00877 Hom.: 5

Bravo AF: 0.00627

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	3.7
DANN	Benign	0.57
PhyloP100		0.91
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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;