Genetic Variant D2HGDH:p.Ala420Pro (chr2-241755966-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_152783.5(D2HGDH):c.1258G>C(p.Ala420Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. A420T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

D2HGDH
NM_152783.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.441

Publications

9 publications found

Variant links:

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: G2P, Labcorp Genetics (formerly Invitae)
D-2-hydroxyglutaric aciduria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

D2HGDH links:

ENSG00000234793 (HGNC:):

ENSG00000234793 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_152783.5

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
D2HGDH	NM_152783.5	MANE Select	c.1258G>C	p.Ala420Pro	missense	Exon 9 of 10	NP_689996.4
D2HGDH	NM_001287249.2		c.856G>C	p.Ala286Pro	missense	Exon 8 of 9	NP_001274178.1	B5MCV2
D2HGDH	NM_001352824.2		c.697G>C	p.Ala233Pro	missense	Exon 9 of 10	NP_001339753.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.1258G>C	p.Ala420Pro	missense	Exon 9 of 10	ENSP00000315351.4	Q8N465-1
D2HGDH	ENST00000436747.5	TSL:1	n.*2494G>C		non_coding_transcript_exon	Exon 11 of 12	ENSP00000400212.1	F8WCF9
D2HGDH	ENST00000468064.5	TSL:1	n.1148G>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.19

CADD

Benign

5.7

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.6

PhyloP100

0.44

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.37

Sift

Benign

0.075

Sift4G

Benign

0.12

Polyphen

0.0080

Vest4

0.56

MutPred

0.56

Loss of helix (P = 0.0072)

MVP

0.76

MPC

0.50

ClinPred

0.077

GERP RS

0.86

Varity_R

0.52

gMVP

0.86

Mutation Taster

=79/21

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over