rs492594

Positions:

• chr2-168907666-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021176.3(G6PC2):​c.655G>C​(p.Val219Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 1,613,228 control chromosomes in the GnomAD database, including 176,336 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (14926 hom., cov: 31)
  • Exomes 𝑓: 0.47 (161410 hom.)
• Consequence: G6PC2 NM_021176.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17

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]

G6PC2 (HGNC:):

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.205058E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC2	NM_021176.3	c.655G>C	p.Val219Leu	missense_variant	5/5	ENST00000375363.8	NP_066999.1
G6PC2	XM_011511564.4	c.427G>C	p.Val143Leu	missense_variant	3/3		XP_011509866.1
G6PC2	XM_011511565.4	c.307G>C	p.Val103Leu	missense_variant	4/4		XP_011509867.1
G6PC2	NM_001081686.2	c.*74G>C		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.655G>C	p.Val219Leu	missense_variant	5/5	1	NM_021176.3	ENSP00000364512.3

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65775 AN: 151728 Hom.: 14925 Cov.: 31

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.443

GnomAD3 exomes AF: 0.498 AC: 125219 AN: 251458 Hom.: 32625 AF XY: 0.499 AC XY: 67830 AN XY: 135896

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.660

Gnomad ASJ exome AF: 0.513

Gnomad EAS exome AF: 0.426

Gnomad SAS exome AF: 0.608

Gnomad FIN exome AF: 0.519

Gnomad NFE exome AF: 0.453

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.465 AC: 680170 AN: 1461382 Hom.: 161410 Cov.: 41 AF XY: 0.469 AC XY: 340807 AN XY: 727034

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.643

Gnomad4 ASJ exome AF: 0.510

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.471

GnomAD4 genome AF: 0.433 AC: 65800 AN: 151846 Hom.: 14926 Cov.: 31 AF XY: 0.442 AC XY: 32773 AN XY: 74156

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.537

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.438

Gnomad4 SAS AF: 0.608

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.449

Gnomad4 OTH AF: 0.438

Alfa AF: 0.450 Hom.: 12084

Bravo AF: 0.431

TwinsUK AF: 0.440 AC: 1632

ALSPAC AF: 0.448 AC: 1727

ESP6500AA AF: 0.321 AC: 1416

ESP6500EA AF: 0.456 AC: 3923

ExAC AF: 0.486 AC: 59040

Asia WGS AF: 0.489 AC: 1702 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.58
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000092	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.57	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.032
MPC		0.030
ClinPred		0.0046	T
GERP RS		3.1
Varity_R		0.031
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs492594; hg19: chr2-169764176; COSMIC: COSV56371655;