17-42910986-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The ENST00000253801.7(G6PC1):​c.634A>T​(p.Ile212Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I212V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

G6PC1
ENST00000253801.7 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 2.27
Variant links:
Genes affected
G6PC1 (HGNC:4056): (glucose-6-phosphatase catalytic subunit 1) Glucose-6-phosphatase (G6Pase) is a multi-subunit integral membrane protein of the endoplasmic reticulum that is composed of a catalytic subunit and transporters for G6P, inorganic phosphate, and glucose. This gene (G6PC) is one of the three glucose-6-phosphatase catalytic-subunit-encoding genes in human: G6PC, G6PC2 and G6PC3. Glucose-6-phosphatase catalyzes the hydrolysis of D-glucose 6-phosphate to D-glucose and orthophosphate and is a key enzyme in glucose homeostasis, functioning in gluconeogenesis and glycogenolysis. Mutations in this gene cause glycogen storage disease type I (GSD1). This disease, also known as von Gierke disease, is a metabolic disorder characterized by severe hypoglycemia associated with the accumulation of glycogen and fat in the liver and kidneys.[provided by RefSeq, Feb 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a transmembrane_region Helical (size 20) in uniprot entity G6PC1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000253801.7
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28422278).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
G6PC1NM_000151.4 linkuse as main transcriptc.634A>T p.Ile212Phe missense_variant 5/5 ENST00000253801.7 NP_000142.2
G6PC1NM_001270397.2 linkuse as main transcriptc.*26A>T 3_prime_UTR_variant 5/5 NP_001257326.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
G6PC1ENST00000253801.7 linkuse as main transcriptc.634A>T p.Ile212Phe missense_variant 5/51 NM_000151.4 ENSP00000253801 P1P35575-1
G6PC1ENST00000585489.1 linkuse as main transcriptc.*26A>T 3_prime_UTR_variant 4/45 ENSP00000466202
G6PC1ENST00000592383.5 linkuse as main transcriptc.*26A>T 3_prime_UTR_variant 5/52 ENSP00000465958 P35575-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251240
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135766
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727246
show subpopulations
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:
0.0000189
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jan 20, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 30, 2021This sequence change replaces isoleucine with phenylalanine at codon 212 of the G6PC protein (p.Ile212Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with G6PC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.0036
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
13
DANN
Benign
0.89
DEOGEN2
Uncertain
0.59
D
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.80
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Uncertain
0.92
D
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.28
T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
1.4
L
MutationTaster
Benign
0.55
D;D;D
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.16
Sift
Uncertain
0.029
D
Sift4G
Benign
0.10
T
Polyphen
0.18
B
Vest4
0.31
MutPred
0.38
Gain of helix (P = 0.0325);
MVP
0.54
MPC
0.41
ClinPred
0.12
T
GERP RS
0.24
Varity_R
0.12
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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.

Other links and lift over

dbSNP: rs756944737; hg19: chr17-41063003; API