2-168901489-T-C

Position:

• chr2-168901489-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021176.3(G6PC2):​c.158T>C​(p.Val53Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,447,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: G6PC2 NM_021176.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38427603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC2	NM_021176.3	c.158T>C	p.Val53Ala	missense_variant	1/5	ENST00000375363.8	NP_066999.1
G6PC2	NM_001081686.2	c.158T>C	p.Val53Ala	missense_variant	1/4		NP_001075155.1
G6PC2	XM_011511564.4	c.158T>C	p.Val53Ala	missense_variant	1/3		XP_011509866.1
G6PC2	XM_011511565.4	c.-81T>C		5_prime_UTR_variant	1/4		XP_011509867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC2	ENST00000375363.8	c.158T>C	p.Val53Ala	missense_variant	1/5	1	NM_021176.3	ENSP00000364512	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447070 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 720908

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: 9.10e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

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

Aug 11, 2022

The c.158T>C (p.V53A) alteration is located in exon 1 (coding exon 1) of the G6PC2 gene. This alteration results from a T to C substitution at nucleotide position 158, causing the valine (V) at amino acid position 53 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D;D;T
Sift4G	Benign	0.20	T;T;D
Polyphen		0.013	B;.;.
Vest4		0.28
MutPred		0.56		Loss of stability (P = 0.0995);Loss of stability (P = 0.0995);Loss of stability (P = 0.0995);
MVP		0.85
MPC		0.17
ClinPred		0.90	D
GERP RS		5.6
Varity_R		0.14
gMVP		0.71

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: rs868267884; hg19: chr2-169757999;