2-168907702-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021176.3(G6PC2):c.691G>A(p.Asp231Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

G6PC2
NM_021176.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.83

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC2	NM_021176.3 link	c.691G>A	p.Asp231Asn	missense_variant	Exon 5 of 5	ENST00000375363.8	NP_066999.1	Q9NQR9-1
G6PC2	XM_011511564.4 link	c.463G>A	p.Asp155Asn	missense_variant	Exon 3 of 3		XP_011509866.1
G6PC2	XM_011511565.4 link	c.343G>A	p.Asp115Asn	missense_variant	Exon 4 of 4		XP_011509867.1
G6PC2	NM_001081686.2 link	c.*110G>A		3_prime_UTR_variant	Exon 4 of 4		NP_001075155.1	Q9NQR9-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC2	ENST00000375363.8 link	c.691G>A	p.Asp231Asn	missense_variant	Exon 5 of 5	1	NM_021176.3	ENSP00000364512.3		Q9NQR9-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.691G>A (p.D231N) 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 691, causing the aspartic acid (D) at amino acid position 231 to be replaced by an asparagine (N). 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

0.16

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

3.2

PhyloP100

9.8

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.64

Sift

Uncertain

0.0020

Sift4G

Benign

0.075

Polyphen

1.0

Vest4

0.81

MutPred

0.73

Loss of stability (P = 0.0442);

MVP

0.77

MPC

0.21

ClinPred

1.0

GERP RS

5.9

Varity_R

0.60

gMVP

0.85

Mutation Taster

=26/74

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over