7-44624507-C-G

Variant names:

• chr7-44624507-C-G
• rs2230445
• NM_002541.4:c.164C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002541.4(OGDH):​c.164C>G​(p.Ser55Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S55L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: OGDH NM_002541.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• Publications: 15 publications found

Genes affected

OGDH (HGNC:8124): (oxoglutarate dehydrogenase) This gene encodes one subunit of the 2-oxoglutarate dehydrogenase complex. This complex catalyzes the overall conversion of 2-oxoglutarate (alpha-ketoglutarate) to succinyl-CoA and CO(2) during the Krebs cycle. The protein is located in the mitochondrial matrix and uses thiamine pyrophosphate as a cofactor. A congenital deficiency in 2-oxoglutarate dehydrogenase activity is believed to lead to hypotonia, metabolic acidosis, and hyperlactatemia. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Sep 2009]

OGDH Gene-Disease associations (from GenCC):

• oxoglutaricaciduria

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002541.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OGDH	NM_002541.4	MANE Select	c.164C>G	p.Ser55Trp	missense	Exon 2 of 23	NP_002532.2	Q02218-1
	OGDH	NM_001439007.1		c.164C>G	p.Ser55Trp	missense	Exon 2 of 24	NP_001425936.1
	OGDH	NM_001363523.2		c.164C>G	p.Ser55Trp	missense	Exon 2 of 24	NP_001350452.1	E9PDF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OGDH	ENST00000222673.6	TSL:1 MANE Select	c.164C>G	p.Ser55Trp	missense	Exon 2 of 23	ENSP00000222673.5	Q02218-1
	OGDH	ENST00000443864.6	TSL:1	c.164C>G	p.Ser55Trp	missense	Exon 2 of 9	ENSP00000388084.2	Q02218-3
	OGDH	ENST00000962345.1		c.164C>G	p.Ser55Trp	missense	Exon 2 of 25	ENSP00000632404.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.019	D
Polyphen		0.95	P
Vest4		0.68
MutPred		0.51		Loss of disorder (P = 0.0048)
MVP		0.55
MPC		1.2
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.89
gMVP		0.85
Mutation Taster		=80/20	polymorphism

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: rs2230445; hg19: chr7-44664106;