2-176330583-G-C

Position:

• chr2-176330583-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006554.5(MTX2):​c.544-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTX2 NM_006554.5 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.79

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.6, offset of 7, new splice context is: ttgcctgtgttacgtcttAGagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-176330583-G-C is Pathogenic according to our data. Variant chr2-176330583-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 805939.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTX2	NM_006554.5	c.544-1G>C		splice_acceptor_variant		ENST00000249442.11	NP_006545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTX2	ENST00000249442.11	c.544-1G>C		splice_acceptor_variant		1	NM_006554.5	ENSP00000249442	P1
MTX2	ENST00000420864.5	c.*634-1G>C		splice_acceptor_variant, NMD_transcript_variant		1		ENSP00000403545
MTX2	ENST00000443241.5	c.376-1G>C		splice_acceptor_variant		3		ENSP00000414176
MTX2	ENST00000452865.1	c.475-1G>C		splice_acceptor_variant		3		ENSP00000398757

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Progeroid mandibuloacral dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Marseille Medical Genetics, U1251, Aix Marseille University, Inserm

Feb 01, 2017

- -

Mandibuloacral dysplasia progeroid syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.79		Position offset: 8
DS_AL_spliceai		0.89		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1575062905; hg19: chr2-177195311;