2-63589392-A-G

Position:

• chr2-63589392-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001199111.2(MDH1):​c.57+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,550,354 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (1 hom.)
• Consequence: MDH1 NM_001199111.2 splice_region, intron
• Scores: Splicing: ADA: 0.00006381
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.475

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]

MDH1 (HGNC:):

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 2-63589392-A-G is Benign according to our data. Variant chr2-63589392-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3067236.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDH1	NM_005917.4	c.3+346A>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+346A>G		intron_variant		1	NM_005917.4	ENSP00000233114.8

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00123 AC: 184 AN: 149358 Hom.: 0 AF XY: 0.00121 AC XY: 97 AN XY: 80432

Gnomad AFR exome AF: 0.000296

Gnomad AMR exome AF: 0.000976

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000532

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.000927

GnomAD4 exome AF: 0.00258 AC: 3601 AN: 1398048 Hom.: 1 Cov.: 31 AF XY: 0.00249 AC XY: 1717 AN XY: 689562

Gnomad4 AFR exome AF: 0.000506

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000644

Gnomad4 FIN exome AF: 0.000997

Gnomad4 NFE exome AF: 0.00304

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00153 AC XY: 114 AN XY: 74472

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00246

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

MDH1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.8
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.010
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: rs201758772; hg19: chr2-63816526;