7-76048186-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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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]

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	UniProt
MDH2	NM_005918.4	c.26C>T	p.Ala9Val	missense_variant	1/9	ENST00000315758.10
MDH2	NM_001282403.2	c.26C>T	p.Ala9Val	missense_variant	1/8
MDH2	NM_001282404.2	c.-127C>T		5_prime_UTR_variant	1/8
MDH2	NR_104165.2	n.81C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDH2	ENST00000315758.10	c.26C>T	p.Ala9Val	missense_variant	1/9	1	NM_005918.4	P1

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

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
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
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.67	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;