2-63590306-A-G

Position:

• chr2-63590306-A-G

Variant summary

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

The NM_005917.4(MDH1):​c.3+1260A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 152,172 control chromosomes in the GnomAD database, including 49,755 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 0.80 (49754 hom., cov: 31)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: MDH1 NM_005917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.176

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDH1	NM_005917.4	c.3+1260A>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.3+1260A>G		intron_variant		1	NM_005917.4	ENSP00000233114	P1

Frequencies

GnomAD3 genomes AF: 0.803 AC: 122098 AN: 152052 Hom.: 49684 Cov.: 31

Gnomad AFR AF: 0.922

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.983

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.768

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 AF XY: 1.00 AC XY: 2 AN XY: 2

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.803 AC: 122232 AN: 152170 Hom.: 49754 Cov.: 31 AF XY: 0.807 AC XY: 60029 AN XY: 74404

Gnomad4 AFR AF: 0.922

Gnomad4 AMR AF: 0.824

Gnomad4 ASJ AF: 0.795

Gnomad4 EAS AF: 0.982

Gnomad4 SAS AF: 0.834

Gnomad4 FIN AF: 0.778

Gnomad4 NFE AF: 0.715

Gnomad4 OTH AF: 0.771

Alfa AF: 0.694 Hom.: 4948

Bravo AF: 0.811

Asia WGS AF: 0.903 AC: 3142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.8
DANN	Benign	0.47

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: rs6546019; hg19: chr2-63817440;