rs161628

Variant names:

• chr17-42907614-G-A
• rs161628
• NM_000151.4:c.432G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-42907614-G-A
• chr17-42907614-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001270397.2(G6PC1):​c.355G>A​(p.Asp119Asn) variant causes a missense 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. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D119H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (126 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (120 hom.)
• Consequence: G6PC1 NM_001270397.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.442
• Publications: 6 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: G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• glycogen storage disease I

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 0.2658 (below the threshold of 3.09). Trascript score misZ: 0.66038 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to glucose-6-phosphatase deficiency type IA.
• 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 Benign/Likely_benign. ClinVar VariationId is 214458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0747 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270397.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC1	NM_000151.4	MANE Select	c.432G>A	p.Pro144Pro	synonymous	Exon 3 of 5	NP_000142.2	P35575-1
	G6PC1	NM_001270397.2		c.355G>A	p.Asp119Asn	missense	Exon 3 of 5	NP_001257326.1	P35575-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC1	ENST00000253801.7	TSL:1 MANE Select	c.432G>A	p.Pro144Pro	synonymous	Exon 3 of 5	ENSP00000253801.1	P35575-1
	G6PC1	ENST00000887112.1		c.355G>A	p.Asp119Asn	missense	Exon 3 of 5	ENSP00000557171.1
	G6PC1	ENST00000592383.5	TSL:2	c.355G>A	p.Asp119Asn	missense	Exon 3 of 5	ENSP00000465958.1	P35575-2

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

GnomAD2 exomes AF: 0.00584 AC: 1464 AN: 250692 AF XY: 0.00420

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 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

African (AFR) AF: 0.0788 AC: 2634 AN: 33436

American (AMR) AF: 0.00486 AC: 217 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5766

European-Non Finnish (NFE) AF: 0.000149 AC: 166 AN: 1111292

Other (OTH) AF: 0.00545 AC: 329 AN: 60362

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

African (AFR) AF: 0.0769 AC: 3195 AN: 41540

American (AMR) AF: 0.00949 AC: 145 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68022

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0129 Hom.: 110

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA (3)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
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
PhyloP100		-0.44
Sift4G	Benign	0.77	T
Vest4		0.15
MVP		0.97
GERP RS		-6.9
Mutation Taster		=97/3	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: rs161628; hg19: chr17-41059631; COSMIC: COSV53831003; COSMIC: COSV53831003;