rs121434362

Positions:

• chr2-241767718-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000321264.9(D2HGDH):​c.1315A>G​(p.Asn439Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: D2HGDH ENST00000321264.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.46

Genes affected

D2HGDH (HGNC:28358): (D-2-hydroxyglutarate dehydrogenase) This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase type 4 family. This enzyme, which is most active in liver and kidney but also active in heart and brain, converts D-2-hydroxyglutarate to 2-ketoglutarate. Mutations in this gene are present in D-2-hydroxyglutaric aciduria, a rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a strand (size 9) in uniprot entity D2HDH_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000321264.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 2-241767718-A-G is Pathogenic according to our data. Variant chr2-241767718-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1856.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-241767718-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
D2HGDH	NM_152783.5	c.1315A>G	p.Asn439Asp	missense_variant	10/10	ENST00000321264.9	NP_689996.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
D2HGDH	ENST00000321264.9	c.1315A>G	p.Asn439Asp	missense_variant	10/10	1	NM_152783.5	ENSP00000315351	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.051	T;D
Polyphen		0.97	D;.
Vest4		0.97
MutPred		0.95		Loss of sheet (P = 0.0228);.;
MVP		0.93
MPC		1.2
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.84
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121434362; hg19: chr2-242707133;