2-156513449-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (1 hom.)
• Consequence: GPD2 NM_000408.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91

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]

ACMG classification

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	UniProt
GPD2	NM_000408.5	c.614C>T	p.Pro205Leu	missense_variant	6/17	ENST00000438166.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPD2	ENST00000438166.7	c.614C>T	p.Pro205Leu	missense_variant	6/17	1	NM_000408.5	P1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 223 AN: 150960 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00124 AC XY: 169 AN XY: 135812

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.: 1 Cov.: 31 AF XY: 0.00236 AC XY: 1718 AN XY: 726908

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.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 109 AN XY: 73580

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.: 0

Bravo AF: 0.00116

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00134 AC: 163

EpiCase AF: 0.00240

EpiControl AF: 0.00255

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2017	- -
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	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	29
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	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
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	D
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

Other links and lift over

dbSNP: rs142821701; hg19: chr2-157369961; COSMIC: COSV99080123; COSMIC: COSV99080123;