17-42911449-T-C

Position:

• chr17-42911449-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000151.4(G6PC1):​c.*23T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,613,692 control chromosomes in the GnomAD database, including 467,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40789 hom., cov: 31)
  • Exomes 𝑓: 0.76 (426315 hom.)
• Consequence: G6PC1 NM_000151.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.696

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-42911449-T-C is Benign according to our data. Variant chr17-42911449-T-C is described in ClinVar as [Benign]. Clinvar id is 255350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC1	NM_000151.4	c.*23T>C		3_prime_UTR_variant	5/5	ENST00000253801.7
G6PC1	NM_001270397.2	c.*489T>C		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC1	ENST00000253801.7	c.*23T>C		3_prime_UTR_variant	5/5	1	NM_000151.4	P1
G6PC1	ENST00000585489.1	c.*489T>C		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110626 AN: 151990 Hom.: 40789 Cov.: 31

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.732

GnomAD3 exomes AF: 0.708 AC: 176095 AN: 248560 Hom.: 63936 AF XY: 0.714 AC XY: 96485 AN XY: 135040

Gnomad AFR exome AF: 0.685

Gnomad AMR exome AF: 0.575

Gnomad ASJ exome AF: 0.778

Gnomad EAS exome AF: 0.449

Gnomad SAS exome AF: 0.654

Gnomad FIN exome AF: 0.812

Gnomad NFE exome AF: 0.783

Gnomad OTH exome AF: 0.734

GnomAD4 exome AF: 0.760 AC: 1110785 AN: 1461584 Hom.: 426315 Cov.: 58 AF XY: 0.758 AC XY: 551463 AN XY: 727110

Gnomad4 AFR exome AF: 0.687

Gnomad4 AMR exome AF: 0.584

Gnomad4 ASJ exome AF: 0.776

Gnomad4 EAS exome AF: 0.446

Gnomad4 SAS exome AF: 0.654

Gnomad4 FIN exome AF: 0.815

Gnomad4 NFE exome AF: 0.787

Gnomad4 OTH exome AF: 0.744

GnomAD4 genome AF: 0.727 AC: 110656 AN: 152108 Hom.: 40789 Cov.: 31 AF XY: 0.721 AC XY: 53647 AN XY: 74362

Gnomad4 AFR AF: 0.687

Gnomad4 AMR AF: 0.624

Gnomad4 ASJ AF: 0.779

Gnomad4 EAS AF: 0.455

Gnomad4 SAS AF: 0.638

Gnomad4 FIN AF: 0.816

Gnomad4 NFE AF: 0.783

Gnomad4 OTH AF: 0.732

Alfa AF: 0.767 Hom.: 96164

Bravo AF: 0.714

Asia WGS AF: 0.560 AC: 1950 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 12, 2018	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	This variant is associated with the following publications: (PMID: 33101979, 28502559) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs2229611; hg19: chr17-41063466; COSMIC: COSV53829988; COSMIC: COSV53829988;