2-168908046-G-A

Position:

• chr2-168908046-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000375363.8(G6PC2):​c.1035G>A​(p.Met345Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: G6PC2 ENST00000375363.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.147

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07481769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC2	NM_021176.3	c.1035G>A	p.Met345Ile	missense_variant	5/5	ENST00000375363.8	NP_066999.1
G6PC2	XM_011511564.4	c.807G>A	p.Met269Ile	missense_variant	3/3		XP_011509866.1
G6PC2	XM_011511565.4	c.687G>A	p.Met229Ile	missense_variant	4/4		XP_011509867.1
G6PC2	NM_001081686.2	c.*454G>A		3_prime_UTR_variant	4/4		NP_001075155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC2	ENST00000375363.8	c.1035G>A	p.Met345Ile	missense_variant	5/5	1	NM_021176.3	ENSP00000364512	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460986 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 01, 2023

The c.1035G>A (p.M345I) 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 1035, causing the methionine (M) at amino acid position 345 to be replaced by an isoleucine (I). 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	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	4.2
DANN	Benign	0.64
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.17
Sift	Benign	0.43	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.32		Loss of MoRF binding (P = 0.0733);
MVP		0.53
MPC		0.032
ClinPred		0.096	T
GERP RS		4.0
Varity_R		0.084
gMVP		0.16

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: rs993287550; hg19: chr2-169764556;