2-168907981-T-C

Position:

chr2-168907981-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021176.3(G6PC2):c.970T>C(p.Ser324Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00286 in 1,613,910 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 50 hom. )

Consequence

G6PC2
NM_021176.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 6.08

Variant links:

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 links:

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]

SPC25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01595375).

BP6

Variant 2-168907981-T-C is Benign according to our data. Variant chr2-168907981-T-C is described in ClinVar as [Benign]. Clinvar id is 3044109.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00379 (577/152368) while in subpopulation EAS AF= 0.0414 (215/5188). AF 95% confidence interval is 0.0369. There are 3 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
G6PC2	NM_021176.3 linkuse as main transcript	c.970T>C	p.Ser324Pro	missense_variant	5/5	ENST00000375363.8	NP_066999.1
G6PC2	XM_011511564.4 linkuse as main transcript	c.742T>C	p.Ser248Pro	missense_variant	3/3		XP_011509866.1
G6PC2	XM_011511565.4 linkuse as main transcript	c.622T>C	p.Ser208Pro	missense_variant	4/4		XP_011509867.1
G6PC2	NM_001081686.2 linkuse as main transcript	c.*389T>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 linkuse as main transcript	c.970T>C	p.Ser324Pro	missense_variant	5/5	1	NM_021176.3	ENSP00000364512	P1	Q9NQR9-1

Frequencies

GnomAD3 genomes

AF:

0.00380

AC:

578

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0415

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00505

AC:

1271

AN:

251468

Hom.:

AF XY:

0.00475

AC XY:

646

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0466

Gnomad SAS exome

AF:

0.00144

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00276

AC:

4038

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

1978

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.00378

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.0347

Gnomad4 SAS exome

AF:

0.00196

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.00168

Gnomad4 OTH exome

AF:

0.00537

GnomAD4 genome

AF:

0.00379

AC:

577

AN:

152368

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

299

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.00296

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.0414

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00313

Hom.:

Bravo

AF:

0.00417

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00457

AC:

555

Asia WGS

AF:

0.0320

AC:

112

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

G6PC2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 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

Pathogenic

0.61

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.016

MetaSVM

Uncertain

0.039

MutationAssessor

Pathogenic

3.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.57

Sift

Uncertain

0.0040

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.94

MVP

0.82

MPC

0.26

ClinPred

0.023

GERP RS

5.8

Varity_R

0.81

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over