2-63595651-T-C

Variant names:

• chr2-63595651-T-C
• rs2305157
• NM_005917.4:c.199+132T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

WDPCP Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 15

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• heart defect - tongue hamartoma - polysyndactyly syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MDH1	NM_005917.4	c.199+132T>C		intron_variant	Intron 3 of 8	ENST00000233114.13	NP_005908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDH1	ENST00000233114.13	c.199+132T>C		intron_variant	Intron 3 of 8	1	NM_005917.4	ENSP00000233114.8

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

African (AFR) AF: 0.947 AC: 12169 AN: 12848

American (AMR) AF: 0.850 AC: 17586 AN: 20680

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 11375 AN: 14336

East Asian (EAS) AF: 0.982 AC: 30700 AN: 31250

South Asian (SAS) AF: 0.833 AC: 39090 AN: 46902

European-Finnish (FIN) AF: 0.777 AC: 31617 AN: 40668

Middle Eastern (MID) AF: 0.754 AC: 1826 AN: 2422

European-Non Finnish (NFE) AF: 0.713 AC: 202931 AN: 284672

Other (OTH) AF: 0.767 AC: 20726 AN: 27016

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

African (AFR) AF: 0.948 AC: 39404 AN: 41556

American (AMR) AF: 0.833 AC: 12728 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.797 AC: 2767 AN: 3470

East Asian (EAS) AF: 0.982 AC: 5093 AN: 5188

South Asian (SAS) AF: 0.835 AC: 4029 AN: 4826

European-Finnish (FIN) AF: 0.779 AC: 8238 AN: 10574

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.717 AC: 48758 AN: 67976

Other (OTH) AF: 0.782 AC: 1653 AN: 2114

Alfa AF: 0.761 Hom.: 5791

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
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2305157; hg19: chr2-63822785;