2-168908036-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021176.3(G6PC2):c.1025C>G(p.Ser342Cys) variant causes a missense change. The variant allele was found at a frequency of 0.113 in 1,611,568 control chromosomes in the GnomAD database, including 17,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (6323 hom., cov: 32)
  • Exomes 𝑓: 0.10 (11592 hom.)
• Consequence: G6PC2 NM_021176.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.76

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.64181E-4).
• BP6: Variant 2-168908036-C-G is Benign according to our data. Variant chr2-168908036-C-G is described in ClinVar as [Benign]. Clinvar id is 3059418.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC2	NM_021176.3	c.1025C>G	p.Ser342Cys	missense_variant	5/5	ENST00000375363.8
G6PC2	XM_011511564.4	c.797C>G	p.Ser266Cys	missense_variant	3/3
G6PC2	XM_011511565.4	c.677C>G	p.Ser226Cys	missense_variant	4/4
G6PC2	NM_001081686.2	c.*444C>G		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC2	ENST00000375363.8	c.1025C>G	p.Ser342Cys	missense_variant	5/5	1	NM_021176.3	P1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32369 AN: 151966 Hom.: 6300 Cov.: 32

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0960

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.0561

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0979

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.117 AC: 29449 AN: 251196 Hom.: 3441 AF XY: 0.105 AC XY: 14223 AN XY: 135794

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.0981

Gnomad EAS exome AF: 0.0245

Gnomad SAS exome AF: 0.0270

Gnomad FIN exome AF: 0.0596

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.103 AC: 150363 AN: 1459484 Hom.: 11592 Cov.: 31 AF XY: 0.0988 AC XY: 71716 AN XY: 726154

Gnomad4 AFR exome AF: 0.527

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.0999

Gnomad4 EAS exome AF: 0.0220

Gnomad4 SAS exome AF: 0.0285

Gnomad4 FIN exome AF: 0.0596

Gnomad4 NFE exome AF: 0.0979

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.213 AC: 32440 AN: 152084 Hom.: 6323 Cov.: 32 AF XY: 0.205 AC XY: 15234 AN XY: 74352

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.0960

Gnomad4 EAS AF: 0.0216

Gnomad4 SAS AF: 0.0338

Gnomad4 FIN AF: 0.0561

Gnomad4 NFE AF: 0.0979

Gnomad4 OTH AF: 0.191

Alfa AF: 0.126 Hom.: 711

Bravo AF: 0.241

TwinsUK AF: 0.0909 AC: 337

ALSPAC AF: 0.0981 AC: 378

ESP6500AA AF: 0.502 AC: 2210

ESP6500EA AF: 0.0916 AC: 788

ExAC AF: 0.123 AC: 14926

Asia WGS AF: 0.0620 AC: 218 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.103

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

G6PC2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	12
Dann	Benign	0.49
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.00016	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.9	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	4.0	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.040
MPC		0.030
ClinPred		0.0014	T
GERP RS		4.9
Varity_R		0.068
gMVP		0.18

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: rs2232328; hg19: chr2-169764546; COSMIC: COSV56371765; COSMIC: COSV56371765;