2-63599394-T-G

Variant names:

• chr2-63599394-T-G
• rs7606045
• NM_005917.4:c.498+102T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001316374.2(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_001316374.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.976
• Publications: 4 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316374.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH1	NM_005917.4	MANE Select	c.498+102T>G		intron	N/A	NP_005908.1
	MDH1	NM_001316374.2		c.498+102T>G		intron	N/A	NP_001303303.1
	MDH1	NM_001199111.2		c.552+102T>G		intron	N/A	NP_001186040.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH1	ENST00000233114.13	TSL:1 MANE Select	c.498+102T>G		intron	N/A	ENSP00000233114.8
	MDH1	ENST00000906791.1		c.498+102T>G		intron	N/A	ENSP00000576850.1
	MDH1	ENST00000539945.7	TSL:2	c.498+102T>G		intron	N/A	ENSP00000438144.3

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

African (AFR) AF: 0.650 AC: 15788 AN: 24284

American (AMR) AF: 0.829 AC: 18074 AN: 21810

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 14696 AN: 18728

East Asian (EAS) AF: 0.982 AC: 31960 AN: 32536

South Asian (SAS) AF: 0.825 AC: 46831 AN: 56788

European-Finnish (FIN) AF: 0.779 AC: 32396 AN: 41562

Middle Eastern (MID) AF: 0.719 AC: 2496 AN: 3470

European-Non Finnish (NFE) AF: 0.708 AC: 623787 AN: 880860

Other (OTH) AF: 0.731 AC: 34716 AN: 47494

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

African (AFR) AF: 0.648 AC: 26879 AN: 41488

American (AMR) AF: 0.782 AC: 11954 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 2730 AN: 3470

East Asian (EAS) AF: 0.982 AC: 5096 AN: 5192

South Asian (SAS) AF: 0.822 AC: 3969 AN: 4828

European-Finnish (FIN) AF: 0.778 AC: 8228 AN: 10574

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.712 AC: 48416 AN: 68004

Other (OTH) AF: 0.709 AC: 1495 AN: 2108

Alfa AF: 0.707 Hom.: 13294

Bravo AF: 0.718

Asia WGS AF: 0.873 AC: 3028 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.81
DANN	Benign	0.65
PhyloP100		-0.98
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: rs7606045; hg19: chr2-63826528;