7-76048173-C-G

Variant names:

• chr7-76048173-C-G
• rs1554584437
• NM_005918.4:c.13C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005918.4(MDH2):​c.13C>G​(p.Leu5Val) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L5L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: MDH2 NM_005918.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0170
• 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 (MetaRNN=0.15129262).

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.13C>G	p.Leu5Val	missense	Exon 1 of 9	NP_005909.2
	MDH2	NM_001282403.2		c.13C>G	p.Leu5Val	missense	Exon 1 of 8	NP_001269332.1	P40926-2
	MDH2	NM_001282404.2		c.-140C>G		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.13C>G	p.Leu5Val	missense	Exon 1 of 9	ENSP00000327070.5	P40926-1
	MDH2	ENST00000971443.1		c.13C>G	p.Leu5Val	missense	Exon 1 of 9	ENSP00000641502.1
	MDH2	ENST00000854579.1		c.13C>G	p.Leu5Val	missense	Exon 1 of 9	ENSP00000524638.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.017
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.048
Sift	Benign	0.47	T
Sift4G	Benign	0.34	T
Polyphen		0.010	B
Vest4		0.23
MutPred		0.20		Gain of helix (P = 0.0325)
MVP		0.51
MPC		0.17
ClinPred		0.71	D
GERP RS		0.032
PromoterAI		-0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.086
gMVP		0.53
Mutation Taster		=91/9	polymorphism

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: rs1554584437; hg19: chr7-75677491;