NM_005918.4:c.2T>C

Variant names:

• chr7-76048162-T-C
• rs1306515179
• NM_005918.4:c.2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_005918.4(MDH2):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,536,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: MDH2 NM_005918.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

Genes affected

MDH2 (HGNC:6971): (malate dehydrogenase 2) Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the mitochondria and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

STYXL1 (HGNC:18165): (serine/threonine/tyrosine interacting like 1) Enables protein phosphatase binding activity; protein phosphatase inhibitor activity; and pseudophosphatase activity. Involved in several processes, including negative regulation of phosphoprotein phosphatase activity; negative regulation of stress granule assembly; and positive regulation of intrinsic apoptotic signaling pathway. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 108 codons. Genomic position: 76057971. Lost 0.317 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDH2	NM_005918.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	ENST00000315758.10	NP_005909.2
STYXL1	NM_001317785.2	c.-505A>G		upstream_gene_variant		ENST00000359697.8	NP_001304714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDH2	ENST00000315758.10	c.2T>C	p.Met1?	start_lost	Exon 1 of 9	1	NM_005918.4	ENSP00000327070.5
STYXL1	ENST00000359697.8	c.-505A>G		upstream_gene_variant		1	NM_001317785.2	ENSP00000352726.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000506 AC: 7 AN: 1384202 Hom.: 0 Cov.: 51 AF XY: 0.00000293 AC XY: 2 AN XY: 683326

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the MDH2 mRNA. The next in-frame methionine is located at codon 108. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MDH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1493417). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	.;D;.
Eigen	Benign	-0.0080
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.49	T
PROVEAN	Uncertain	-3.0	.;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.0020	.;D;D
Polyphen		0.016	.;B;.
Vest4		0.73
MutPred		0.96		Gain of phosphorylation at M1 (P = 0.0643);Gain of phosphorylation at M1 (P = 0.0643);Gain of phosphorylation at M1 (P = 0.0643);
MVP		0.89
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.87
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs1306515179; hg19: chr7-75677480;