2-168907862-G-A

Variant names:

• chr2-168907862-G-A
• NM_021176.3:c.851G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021176.3(G6PC2):​c.851G>A​(p.Gly284Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: G6PC2 NM_021176.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.77

Genes affected

G6PC2 (HGNC:28906): (glucose-6-phosphatase catalytic subunit 2) This gene encodes an enzyme belonging to the glucose-6-phosphatase catalytic subunit family. These enzymes are part of a multicomponent integral membrane system that catalyzes the hydrolysis of glucose-6-phosphate, the terminal step in gluconeogenic and glycogenolytic pathways, allowing the release of glucose into the bloodstream. The family member encoded by this gene is found in pancreatic islets and does not exhibit phosphohydrolase activity, but it is a major target of cell-mediated autoimmunity in diabetes. Several alternatively spliced transcript variants of this gene have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

SPC25 (HGNC:24031): (SPC25 component of NDC80 kinetochore complex) This gene encodes a protein that may be involved in kinetochore-microtubule interaction and spindle checkpoint activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC2	NM_021176.3	c.851G>A	p.Gly284Glu	missense_variant	Exon 5 of 5	ENST00000375363.8	NP_066999.1
G6PC2	XM_011511564.4	c.623G>A	p.Gly208Glu	missense_variant	Exon 3 of 3		XP_011509866.1
G6PC2	XM_011511565.4	c.503G>A	p.Gly168Glu	missense_variant	Exon 4 of 4		XP_011509867.1
G6PC2	NM_001081686.2	c.*270G>A		3_prime_UTR_variant	Exon 4 of 4		NP_001075155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC2	ENST00000375363.8	c.851G>A	p.Gly284Glu	missense_variant	Exon 5 of 5	1	NM_021176.3	ENSP00000364512.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.851G>A (p.G284E) alteration is located in exon 5 (coding exon 5) of the G6PC2 gene. This alteration results from a G to A substitution at nucleotide position 851, causing the glycine (G) at amino acid position 284 to be replaced by a glutamic acid (E). 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	Benign	0.10
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.10	T
Sift4G	Benign	0.31	T
Polyphen		0.99	D
Vest4		0.40
MutPred		0.34		Loss of methylation at R283 (P = 0.0424);
MVP		0.70
MPC		0.25
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.27
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-169764372;