2-156549643-G-C

Position:

• chr2-156549643-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000408.5(GPD2):​c.697G>C​(p.Ala233Pro) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPD2 NM_000408.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPD2	NM_000408.5	c.697G>C	p.Ala233Pro	missense_variant	7/17	ENST00000438166.7	NP_000399.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPD2	ENST00000438166.7	c.697G>C	p.Ala233Pro	missense_variant	7/17	1	NM_000408.5	ENSP00000409708.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2024

The c.697G>C (p.A233P) alteration is located in exon 7 (coding exon 6) of the GPD2 gene. This alteration results from a G to C substitution at nucleotide position 697, causing the alanine (A) at amino acid position 233 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;.;D;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.6	H;H;.;H;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D;D;D;D;N
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		0.98	D;D;.;D;.
Vest4		0.93
MutPred		0.90		Loss of stability (P = 0.0897);Loss of stability (P = 0.0897);Loss of stability (P = 0.0897);Loss of stability (P = 0.0897);.;
MVP		0.98
MPC		0.96
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-157406155;