7-76048186-C-T

Position:

• chr7-76048186-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (15748 hom., cov: 35)
  • Exomes 𝑓: 0.33 (82646 hom.)
• Consequence: MDH2 NM_005918.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.423

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 667830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-76048186-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDH2	NM_005918.4	c.26C>T	p.Ala9Val	missense_variant	1/9	ENST00000315758.10	NP_005909.2
MDH2	NM_001282403.2	c.26C>T	p.Ala9Val	missense_variant	1/8		NP_001269332.1
MDH2	NM_001282404.2	c.-127C>T		5_prime_UTR_variant	1/8		NP_001269333.1
MDH2	NR_104165.2	n.81C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDH2	ENST00000315758.10	c.26C>T	p.Ala9Val	missense_variant	1/9	1	NM_005918.4	ENSP00000327070.5

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65360 AN: 152050 Hom.: 15706 Cov.: 35

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

GnomAD3 exomes AF: 0.401 AC: 56807 AN: 141784 Hom.: 12483 AF XY: 0.395 AC XY: 30178 AN XY: 76476

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 SAS exome AF: 0.450

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.: 56 AF XY: 0.335 AC XY: 229237 AN XY: 683570

Gnomad4 AFR exome AF: 0.650

Gnomad4 AMR exome AF: 0.470

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.610

Gnomad4 SAS exome AF: 0.451

Gnomad4 FIN exome AF: 0.413

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.355

GnomAD4 genome AF: 0.430 AC: 65459 AN: 152168 Hom.: 15748 Cov.: 35 AF XY: 0.439 AC XY: 32690 AN XY: 74390

Gnomad4 AFR AF: 0.637

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.600

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.426

Gnomad4 NFE AF: 0.299

Gnomad4 OTH AF: 0.398

Alfa AF: 0.352 Hom.: 1844

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Benign	0.0000076	T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.010	.;N;N
REVEL	Benign	0.063
Sift	Benign	0.15	.;T;T
Sift4G	Benign	0.21	.;T;T
Polyphen		0.0	.;B;.
Vest4		0.040
MPC		0.17
ClinPred		0.0094	T
GERP RS		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.041
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs6720; hg19: chr7-75677504; COSMIC: COSV50388126; COSMIC: COSV50388126;