2-63599394-T-G

Position:

• chr2-63599394-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005917.4(MDH1):​c.498+102T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 1,279,690 control chromosomes in the GnomAD database, including 339,837 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (39888 hom., cov: 34)
  • Exomes 𝑓: 0.73 (299949 hom.)
• Consequence: MDH1 NM_005917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.976

Genes affected

MDH1 (HGNC:6970): (malate dehydrogenase 1) This gene encodes an enzyme that catalyzes the NAD/NADH-dependent, reversible oxidation of malate to oxaloacetate in many metabolic pathways, including the citric acid cycle. Two main isozymes are known to exist in eukaryotic cells: one is found in the mitochondrial matrix and the other in the cytoplasm. This gene encodes the cytosolic isozyme, which plays a key role in the malate-aspartate shuttle that allows malate to pass through the mitochondrial membrane to be transformed into oxaloacetate for further cellular processes. Alternatively spliced transcript variants have been found for this gene. A recent study showed that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is localized in the peroxisomes. Pseudogenes have been identified on chromosomes X and 6. [provided by RefSeq, Feb 2016]

WDPCP (HGNC:28027): (WD repeat containing planar cell polarity effector) This gene encodes a cytoplasmic WD40 repeat protein. A similar gene in frogs encodes a planar cell polarity protein that plays a critical role in collective cell movement and ciliogenesis by mediating septin localization. Mutations in this gene are associated with Bardet-Biedl syndrome 15 and may also play a role in Meckel-Gruber syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

MDH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDH1	NM_005917.4	c.498+102T>G		intron_variant		ENST00000233114.13	NP_005908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDH1	ENST00000233114.13	c.498+102T>G		intron_variant		1	NM_005917.4	ENSP00000233114.8

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109564 AN: 152040 Hom.: 39845 Cov.: 34

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.982

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.712

Gnomad OTH AF: 0.705

GnomAD4 exome AF: 0.728 AC: 820744 AN: 1127532 Hom.: 299949 Cov.: 14 AF XY: 0.730 AC XY: 407486 AN XY: 558138

Gnomad4 AFR exome AF: 0.650

Gnomad4 AMR exome AF: 0.829

Gnomad4 ASJ exome AF: 0.785

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.825

Gnomad4 FIN exome AF: 0.779

Gnomad4 NFE exome AF: 0.708

Gnomad4 OTH exome AF: 0.731

GnomAD4 genome AF: 0.721 AC: 109667 AN: 152158 Hom.: 39888 Cov.: 34 AF XY: 0.726 AC XY: 54027 AN XY: 74396

Gnomad4 AFR AF: 0.648

Gnomad4 AMR AF: 0.782

Gnomad4 ASJ AF: 0.787

Gnomad4 EAS AF: 0.982

Gnomad4 SAS AF: 0.822

Gnomad4 FIN AF: 0.778

Gnomad4 NFE AF: 0.712

Gnomad4 OTH AF: 0.709

Alfa AF: 0.704 Hom.: 7948

Bravo AF: 0.718

Asia WGS AF: 0.873 AC: 3028 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.81
DANN	Benign	0.65

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: rs7606045; hg19: chr2-63826528;