rs2593595

Variant names:

• chr17-42904228-A-G
• rs2593595
• NM_000151.4:c.340+188A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000151.4(G6PC1):​c.340+188A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 602,622 control chromosomes in the GnomAD database, including 32,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (17381 hom., cov: 31)
  • Exomes 𝑓: 0.23 (15308 hom.)
• Consequence: G6PC1 NM_000151.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.871
• Publications: 21 publications found

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]

G6PC1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to glucose-6-phosphatase deficiency type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-42904228-A-G is Benign according to our data. Variant chr17-42904228-A-G is described in ClinVar as Benign. ClinVar VariationId is 1238046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.340+188A>G		intron_variant	Intron 2 of 4	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.340+188A>G		intron_variant	Intron 2 of 4		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801.7	c.340+188A>G		intron_variant	Intron 2 of 4	1	NM_000151.4	ENSP00000253801.1
G6PC1	ENST00000588481.1	n.593A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
G6PC1	ENST00000592383.5	c.340+188A>G		intron_variant	Intron 2 of 4	2		ENSP00000465958.1
G6PC1	ENST00000585489.1	c.340+188A>G		intron_variant	Intron 2 of 3	5		ENSP00000466202.1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58158 AN: 151984 Hom.: 17314 Cov.: 31

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.341

GnomAD4 exome AF: 0.230 AC: 103502 AN: 450520 Hom.: 15308 Cov.: 4 AF XY: 0.232 AC XY: 56358 AN XY: 242578

African (AFR) AF: 0.836 AC: 11039 AN: 13206

American (AMR) AF: 0.280 AC: 8008 AN: 28574

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 3217 AN: 14904

East Asian (EAS) AF: 0.117 AC: 3150 AN: 26902

South Asian (SAS) AF: 0.309 AC: 16371 AN: 52994

European-Finnish (FIN) AF: 0.202 AC: 5352 AN: 26492

Middle Eastern (MID) AF: 0.273 AC: 524 AN: 1916

European-Non Finnish (NFE) AF: 0.190 AC: 49432 AN: 260812

Other (OTH) AF: 0.259 AC: 6409 AN: 24720

GnomAD4 genome AF: 0.383 AC: 58286 AN: 152102 Hom.: 17381 Cov.: 31 AF XY: 0.381 AC XY: 28304 AN XY: 74354

African (AFR) AF: 0.839 AC: 34790 AN: 41460

American (AMR) AF: 0.279 AC: 4259 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3470

East Asian (EAS) AF: 0.155 AC: 804 AN: 5176

South Asian (SAS) AF: 0.318 AC: 1538 AN: 4830

European-Finnish (FIN) AF: 0.203 AC: 2152 AN: 10582

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13034 AN: 67980

Other (OTH) AF: 0.337 AC: 714 AN: 2116

Alfa AF: 0.248 Hom.: 23944

Bravo AF: 0.408

Asia WGS AF: 0.251 AC: 874 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.43
DANN	Benign	0.64
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2593595; hg19: chr17-41056245;