2-63595651-T-C

Position:

• chr2-63595651-T-C

Variant summary

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

The NM_005917.4(MDH1):​c.199+132T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 632,990 control chromosomes in the GnomAD database, including 193,696 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 0.81 (51044 hom., cov: 32)
  • Exomes 𝑓: 0.77 (142652 hom.)
• Consequence: MDH1 NM_005917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40

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=-1.0).
• 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	UniProt
MDH1	NM_005917.4	c.199+132T>C		intron_variant		ENST00000233114.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDH1	ENST00000233114.13	c.199+132T>C		intron_variant		1	NM_005917.4	P1

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123528 AN: 152078 Hom.: 50971 Cov.: 32

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.832

Gnomad ASJ AF: 0.797

Gnomad EAS AF: 0.982

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.779

GnomAD4 exome AF: 0.765 AC: 368020 AN: 480794 Hom.: 142652 AF XY: 0.766 AC XY: 196653 AN XY: 256570

Gnomad4 AFR exome AF: 0.947

Gnomad4 AMR exome AF: 0.850

Gnomad4 ASJ exome AF: 0.793

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.833

Gnomad4 FIN exome AF: 0.777

Gnomad4 NFE exome AF: 0.713

Gnomad4 OTH exome AF: 0.767

GnomAD4 genome AF: 0.813 AC: 123665 AN: 152196 Hom.: 51044 Cov.: 32 AF XY: 0.816 AC XY: 60678 AN XY: 74398

Gnomad4 AFR AF: 0.948

Gnomad4 AMR AF: 0.833

Gnomad4 ASJ AF: 0.797

Gnomad4 EAS AF: 0.982

Gnomad4 SAS AF: 0.835

Gnomad4 FIN AF: 0.779

Gnomad4 NFE AF: 0.717

Gnomad4 OTH AF: 0.782

Alfa AF: 0.754 Hom.: 5449

Bravo AF: 0.822

Asia WGS AF: 0.908 AC: 3158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.072
DANN	Benign	0.61

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: rs2305157; hg19: chr2-63822785;