chr2-156513449-C-T

Position:

chr2-156513449-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000408.5(GPD2):c.614C>T(p.Pro205Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,612,072 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 1 hom. )

Consequence

GPD2
NM_000408.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

GPD2 (HGNC:4456): (glycerol-3-phosphate dehydrogenase 2) The protein encoded by this gene localizes to the inner mitochondrial membrane and catalyzes the conversion of glycerol-3-phosphate to dihydroxyacetone phosphate, using FAD as a cofactor. Along with GDP1, the encoded protein constitutes the glycerol phosphate shuttle, which reoxidizes NADH formed during glycolysis. Two transcript variants encoding the same protein have been found for this gene.[provided by RefSeq, Jan 2010]

GPD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPD2	NM_000408.5 linkuse as main transcript	c.614C>T	p.Pro205Leu	missense_variant	6/17	ENST00000438166.7	NP_000399.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPD2	ENST00000438166.7 linkuse as main transcript	c.614C>T	p.Pro205Leu	missense_variant	6/17	1	NM_000408.5	ENSP00000409708	P1	P43304-1

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

223

AN:

150960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000656

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000264

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00120

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00264

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00130

AC:

327

AN:

251296

Hom.:

AF XY:

0.00124

AC XY:

169

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00250

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00240

AC:

3503

AN:

1461086

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

1718

AN XY:

726908

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00101

Gnomad4 NFE exome

AF:

0.00300

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00148

AC:

223

AN:

150986

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

109

AN XY:

73580

show subpopulations

Gnomad4 AFR

AF:

0.000655

Gnomad4 AMR

AF:

0.000263

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00120

Gnomad4 NFE

AF:

0.00264

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00182

Hom.:

Bravo

AF:

0.00116

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00134

AC:

163

EpiCase

AF:

0.00240

EpiControl

AF:

0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	GPD2: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2017	The P205L variant in the GPD2 gene has been reported previously in a patient with intellectual disability, mild dysmorphism, and a pervasive developmental disorder who was compound heterozygous for the P205L variant and a de novo 298 kb deletion encompassing two genes, including the GPD2 gene (Barge-Schaapveld et al., 2013). The P205L variant was also seen in the patient's healthy mother and sister, who were shown by functional studies to have reduced GPD2 activity (Barge-Schaapveld et al., 2013). The P205L variant is observed in 142/66688 (0.2%) alleles from individuals of non-Finnish European background in the ExAC dataset, and in 1 homozygous presumably healthy individual undergoing testing at GeneDx (Lek et al., 2016). The P205L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P205L as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D;D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

.;.;D;.;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.81

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

H;H;.;H;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-9.1

D;D;D;D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;D;.

Vest4

0.99

MVP

0.97

MPC

0.86

ClinPred

0.98

GERP RS

5.5

Varity_R

0.89

gMVP

0.92

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over