7-76048177-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005918.4(MDH2):c.17C>T(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000013 in 1,536,474 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. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.0000066 ( 0 hom., cov: 35)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

MDH2
NM_005918.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

Publications

0 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: 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=0.1711373).

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.17C>T	p.Ala6Val	missense	Exon 1 of 9	NP_005909.2
MDH2	NM_001282403.2		c.17C>T	p.Ala6Val	missense	Exon 1 of 8	NP_001269332.1	P40926-2
MDH2	NM_001282404.2		c.-136C>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.17C>T	p.Ala6Val	missense	Exon 1 of 9	ENSP00000327070.5	P40926-1
MDH2	ENST00000971443.1		c.17C>T	p.Ala6Val	missense	Exon 1 of 9	ENSP00000641502.1
MDH2	ENST00000854579.1		c.17C>T	p.Ala6Val	missense	Exon 1 of 9	ENSP00000524638.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

142312

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

AF:

7.22e-7

AC:

AN:

1384234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

683340

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31556

American (AMR)

AF:

0.00

AC:

AN:

35992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25152

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

79192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5384

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078594

Other (OTH)

AF:

0.00

AC:

AN:

57848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.79

M_CAP

Benign

0.020

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

PhyloP100

1.8

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.30

REVEL

Benign

0.10

Sift

Benign

0.34

Sift4G

Benign

0.20

Polyphen

0.083

Vest4

0.28

MutPred

0.25

Gain of helix (P = 0.0199)

MVP

0.60

MPC

0.17

ClinPred

0.98

GERP RS

4.7

PromoterAI

0.0040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.12

gMVP

0.47

Mutation Taster

=79/21

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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