rs121434361

Variant names:

• chr2-241742524-T-G
• rs121434361
• NM_152783.5:c.440T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-241742524-T-G
• chr2-241742524-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_152783.5(D2HGDH):​c.440T>G​(p.Ile147Ser) 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: 32)
• Consequence: D2HGDH NM_152783.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.46
• Publications: 10 publications found

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]

D2HGDH Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• D-2-hydroxyglutaric aciduria 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• D-2-hydroxyglutaric aciduria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 2-241742524-T-G is Pathogenic according to our data. Variant chr2-241742524-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1853.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152783.5. 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
	D2HGDH	NM_152783.5	MANE Select	c.440T>G	p.Ile147Ser	missense	Exon 4 of 10	NP_689996.4
	D2HGDH	NM_001287249.2		c.38T>G	p.Ile13Ser	missense	Exon 3 of 9	NP_001274178.1	B5MCV2
	D2HGDH	NM_001352824.2		c.-105T>G		5_prime_UTR	Exon 4 of 10	NP_001339753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.440T>G	p.Ile147Ser	missense	Exon 4 of 10	ENSP00000315351.4	Q8N465-1
	D2HGDH	ENST00000436747.5	TSL:1	n.440T>G		non_coding_transcript_exon	Exon 4 of 12	ENSP00000400212.1	F8WCF9
	D2HGDH	ENST00000951632.1		c.587T>G	p.Ile196Ser	missense	Exon 5 of 12	ENSP00000621691.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000385 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	D-2-hydroxyglutaric aciduria 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.91		Gain of sheet (P = 0.0477)
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs121434361; hg19: chr2-242681939;