7-76048176-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005918.4(MDH2):c.16G>A(p.Ala6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000376 in 1,384,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

MDH2
NM_005918.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.77

Publications

1 publications found

Variant links:

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]

MDH2 links:

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]

STYXL1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15456793).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDH2	NM_005918.4	MANE Select	c.16G>A	p.Ala6Thr	missense	Exon 1 of 9	NP_005909.2
MDH2	NM_001282403.2		c.16G>A	p.Ala6Thr	missense	Exon 1 of 8	NP_001269332.1	P40926-2
MDH2	NM_001282404.2		c.-137G>A		5_prime_UTR	Exon 1 of 8	NP_001269333.1	G3XAL0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDH2	ENST00000315758.10	TSL:1 MANE Select	c.16G>A	p.Ala6Thr	missense	Exon 1 of 9	ENSP00000327070.5	P40926-1
MDH2	ENST00000971443.1		c.16G>A	p.Ala6Thr	missense	Exon 1 of 9	ENSP00000641502.1
MDH2	ENST00000854579.1		c.16G>A	p.Ala6Thr	missense	Exon 1 of 9	ENSP00000524638.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000211

AC:

AN:

142036

AF XY:

0.0000261

show subpopulations

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:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1384174

Hom.:

Cov.:

AF XY:

0.0000424

AC XY:

AN XY:

683308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31556

American (AMR)

AF:

0.00

AC:

AN:

35972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25148

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00

AC:

AN:

79184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5374

European-Non Finnish (NFE)

AF:

0.0000482

AC:

AN:

1078580

Other (OTH)

AF:

0.00

AC:

AN:

57842

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000440

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.095

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.66

M_CAP

Benign

0.017

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

PhyloP100

1.8

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.57

REVEL

Benign

0.064

Sift

Benign

0.34

Sift4G

Benign

0.37

Polyphen

0.20

Vest4

0.14

MutPred

0.25

Gain of phosphorylation at A6 (P = 0.028)

MVP

0.62

MPC

0.17

ClinPred

0.95

GERP RS

3.7

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.056

gMVP

0.46

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over