2-176330641-C-T

Variant names:

• chr2-176330641-C-T
• rs202061018
• NM_006554.5:c.601C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_006554.5(MTX2):​c.601C>T​(p.Pro201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,591,824 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (1 hom.)
• Consequence: MTX2 NM_006554.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027932584).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000463 (7/151066) while in subpopulation EAS AF= 0.00116 (6/5166). AF 95% confidence interval is 0.000506. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTX2	NM_006554.5	c.601C>T	p.Pro201Ser	missense_variant	Exon 9 of 10	ENST00000249442.11	NP_006545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTX2	ENST00000249442.11	c.601C>T	p.Pro201Ser	missense_variant	Exon 9 of 10	1	NM_006554.5	ENSP00000249442.6

Frequencies

GnomAD3 genomes AF: 0.0000464 AC: 7 AN: 150950 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000483

GnomAD3 exomes AF: 0.000129 AC: 32 AN: 248540 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 134420

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00137

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.0000444 AC: 64 AN: 1440758 Hom.: 1 Cov.: 29 AF XY: 0.0000419 AC XY: 30 AN XY: 716746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000584

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000364

Gnomad4 OTH exome AF: 0.000592

GnomAD4 genome AF: 0.0000463 AC: 7 AN: 151066 Hom.: 0 Cov.: 32 AF XY: 0.0000542 AC XY: 4 AN XY: 73796

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000157 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.601C>T (p.P201S) alteration is located in exon 9 (coding exon 9) of the MTX2 gene. This alteration results from a C to T substitution at nucleotide position 601, causing the proline (P) at amino acid position 201 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.032	T;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.96	L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.70	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.0050	B;.;.
Vest4		0.28
MVP		0.36
MPC		0.17
ClinPred		0.029	T
GERP RS		5.6
Varity_R		0.040
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs202061018; hg19: chr2-177195369;