rs161628

Positions:

• chr17-42907614-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000151.4(G6PC1):​c.432G>A​(p.Pro144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,613,148 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P144P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (126 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (120 hom.)
• Consequence: G6PC1 NM_000151.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.442

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032521486).
• BP6: Variant 17-42907614-G-A is Benign according to our data. Variant chr17-42907614-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 214458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42907614-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.442 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC1	NM_000151.4	c.432G>A	p.Pro144=	synonymous_variant	3/5	ENST00000253801.7
G6PC1	NM_001270397.2	c.355G>A	p.Asp119Asn	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC1	ENST00000253801.7	c.432G>A	p.Pro144=	synonymous_variant	3/5	1	NM_000151.4	P1
G6PC1	ENST00000592383.5	c.355G>A	p.Asp119Asn	missense_variant	3/5	2
G6PC1	ENST00000585489.1	c.432G>A	p.Pro144=	synonymous_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3370 AN: 152130 Hom.: 123 Cov.: 31

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00584 AC: 1464 AN: 250692 Hom.: 48 AF XY: 0.00420 AC XY: 569 AN XY: 135462

Gnomad AFR exome AF: 0.0784

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00233 AC: 3401 AN: 1460900 Hom.: 120 Cov.: 30 AF XY: 0.00204 AC XY: 1482 AN XY: 726756

Gnomad4 AFR exome AF: 0.0788

Gnomad4 AMR exome AF: 0.00486

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.00545

GnomAD4 genome AF: 0.0223 AC: 3390 AN: 152248 Hom.: 126 Cov.: 31 AF XY: 0.0214 AC XY: 1593 AN XY: 74446

Gnomad4 AFR AF: 0.0769

Gnomad4 AMR AF: 0.00949

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00759 Hom.: 42

Bravo AF: 0.0252

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0751 AC: 331

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00723 AC: 878

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2017	Variant summary: The G6PC c.432G>A (p.Pro144Pro) variant causes a missense change located in the Phosphatidic acid phosphatase type 2/haloperoxidase domain (IPR000326) (InterPro) involving the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2067/276430 control chromosomes in gnomAD, including 72 homozygous individuals, at a frequency of 0.0074775, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 30, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	3.4
DANN	Benign	0.55
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0033	T
MutationTaster	Benign	0.99	D;D;N
Sift4G	Benign	0.77	T
Vest4		0.15
MVP		0.97
GERP RS		-6.9

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: rs161628; hg19: chr17-41059631; COSMIC: COSV53831003; COSMIC: COSV53831003;