rs6720

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005918.4(MDH2):c.26C>T(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,536,850 control chromosomes in the GnomAD database, including 98,394 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A9A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.43 ( 15748 hom., cov: 35)

Exomes 𝑓: 0.33 ( 82646 hom. )

Consequence

MDH2
NM_005918.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.423

Publications

30 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.642798E-6).

BP6

Variant 7-76048186-C-T is Benign according to our data. Variant chr7-76048186-C-T is described in ClinVar as Benign. ClinVar VariationId is 667830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

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.26C>T	p.Ala9Val	missense	Exon 1 of 9	NP_005909.2
MDH2	NM_001282403.2		c.26C>T	p.Ala9Val	missense	Exon 1 of 8	NP_001269332.1	P40926-2
MDH2	NM_001282404.2		c.-127C>T		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.26C>T	p.Ala9Val	missense	Exon 1 of 9	ENSP00000327070.5	P40926-1
MDH2	ENST00000971443.1		c.26C>T	p.Ala9Val	missense	Exon 1 of 9	ENSP00000641502.1
MDH2	ENST00000854579.1		c.26C>T	p.Ala9Val	missense	Exon 1 of 9	ENSP00000524638.1

Frequencies

GnomAD3 genomes

AF:

0.430

AC:

65360

AN:

152050

Hom.:

15706

Cov.:

show subpopulations

Gnomad AFR

AF:

0.637

Gnomad AMI

AF:

0.400

Gnomad AMR

AF:

0.435

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.601

Gnomad SAS

AF:

0.469

Gnomad FIN

AF:

0.426

Gnomad MID

AF:

0.296

Gnomad NFE

AF:

0.299

Gnomad OTH

AF:

0.396

GnomAD2 exomes

AF:

0.401

AC:

56807

AN:

141784

AF XY:

0.395

show subpopulations

Gnomad AFR exome

AF:

0.656

Gnomad AMR exome

AF:

0.479

Gnomad ASJ exome

AF:

0.253

Gnomad EAS exome

AF:

0.595

Gnomad FIN exome

AF:

0.411

Gnomad NFE exome

AF:

0.299

Gnomad OTH exome

AF:

0.349

GnomAD4 exome

AF:

0.333

AC:

461617

AN:

1384682

Hom.:

82646

Cov.:

AF XY:

0.335

AC XY:

229237

AN XY:

683570

show subpopulations

African (AFR)

AF:

0.650

AC:

20542

AN:

31582

American (AMR)

AF:

0.470

AC:

16939

AN:

36012

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6444

AN:

25168

East Asian (EAS)

AF:

0.610

AC:

21805

AN:

35746

South Asian (SAS)

AF:

0.451

AC:

35755

AN:

79238

European-Finnish (FIN)

AF:

0.413

AC:

14338

AN:

34736

Middle Eastern (MID)

AF:

0.351

AC:

1852

AN:

5270

European-Non Finnish (NFE)

AF:

0.300

AC:

323396

AN:

1079064

Other (OTH)

AF:

0.355

AC:

20546

AN:

57866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

19093

38185

57278

76370

95463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11148

22296

33444

44592

55740

<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

AF:

0.430

AC:

65459

AN:

152168

Hom.:

15748

Cov.:

AF XY:

0.439

AC XY:

32690

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.637

AC:

26458

AN:

41516

American (AMR)

AF:

0.435

AC:

6653

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

885

AN:

3470

East Asian (EAS)

AF:

0.600

AC:

3099

AN:

5162

South Asian (SAS)

AF:

0.467

AC:

2254

AN:

4830

European-Finnish (FIN)

AF:

0.426

AC:

4520

AN:

10600

Middle Eastern (MID)

AF:

0.308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.299

AC:

20295

AN:

67974

Other (OTH)

AF:

0.398

AC:

841

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1832

3663

5495

7326

9158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.359

Hom.:

1985

Bravo

AF:

0.438

TwinsUK

AF:

0.300

AC:

1113

ALSPAC

AF:

0.297

AC:

1145

ESP6500AA

AF:

0.594

AC:

2410

ESP6500EA

AF:

0.287

AC:

2255

ExAC

AF:

0.286

AC:

23429

Asia WGS

AF:

0.533

AC:

1855

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Developmental and epileptic encephalopathy, 51 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0000076

MetaSVM

Benign

-0.98

PhyloP100

0.42

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.010

REVEL

Benign

0.063

Sift

Benign

0.15

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.040

MPC

0.17

ClinPred

0.0094

GERP RS

0.56

PromoterAI

-0.071

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.041

gMVP

0.48

Mutation Taster

=98/2

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over