NM_005918.4:c.6C>A

Variant names:

• chr7-76048166-C-A
• rs1554584427
• NM_005918.4:c.6C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_005918.4(MDH2):​c.6C>A​(p.Leu2Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L2L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MDH2 NM_005918.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0940
• Publications: 0 publications found

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

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 (BayesDel_noAF=-0.18).
• BP7: Synonymous conserved (PhyloP=0.094 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005918.4. 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
	MDH2	NM_005918.4	MANE Select	c.6C>A	p.Leu2Leu	synonymous	Exon 1 of 9	NP_005909.2
	MDH2	NM_001282403.2		c.6C>A	p.Leu2Leu	synonymous	Exon 1 of 8	NP_001269332.1	P40926-2
	MDH2	NM_001282404.2		c.-147C>A		5_prime_UTR	Exon 1 of 8	NP_001269333.1	G3XAL0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH2	ENST00000315758.10	TSL:1 MANE Select	c.6C>A	p.Leu2Leu	synonymous	Exon 1 of 9	ENSP00000327070.5	P40926-1
	MDH2	ENST00000971443.1		c.6C>A	p.Leu2Leu	synonymous	Exon 1 of 9	ENSP00000641502.1
	MDH2	ENST00000854579.1		c.6C>A	p.Leu2Leu	synonymous	Exon 1 of 9	ENSP00000524638.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00 AC: 0 AN: 142908 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1384204 Hom.: 0 Cov.: 52 AF XY: 0.00 AC XY: 0 AN XY: 683320

African (AFR) AF: 0.00 AC: 0 AN: 31558

American (AMR) AF: 0.00 AC: 0 AN: 35942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.00 AC: 0 AN: 79170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078526

Other (OTH) AF: 0.00 AC: 0 AN: 57844

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	9.6
DANN	Benign	0.90
PhyloP100		0.094
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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

Other links and lift over

dbSNP: rs1554584427; hg19: chr7-75677484;