2-168906660-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_021176.3(G6PC2):c.441-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000554 in 1,470,228 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: G6PC2 NM_021176.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002811
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.126

Genes affected

G6PC2 (HGNC:28906): (glucose-6-phosphatase catalytic subunit 2) This gene encodes an enzyme belonging to the glucose-6-phosphatase catalytic subunit family. These enzymes are part of a multicomponent integral membrane system that catalyzes the hydrolysis of glucose-6-phosphate, the terminal step in gluconeogenic and glycogenolytic pathways, allowing the release of glucose into the bloodstream. The family member encoded by this gene is found in pancreatic islets and does not exhibit phosphohydrolase activity, but it is a major target of cell-mediated autoimmunity in diabetes. Several alternatively spliced transcript variants of this gene have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

SPC25 (HGNC:24031): (SPC25 component of NDC80 kinetochore complex) This gene encodes a protein that may be involved in kinetochore-microtubule interaction and spindle checkpoint activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-168906660-G-A is Benign according to our data. Variant chr2-168906660-G-A is described in ClinVar as [Benign]. Clinvar id is 3039044.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC2	NM_021176.3	c.441-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000375363.8
G6PC2	NM_001081686.2	c.441-908G>A		intron_variant
G6PC2	XM_011511564.4	c.329-908G>A		intron_variant
G6PC2	XM_011511565.4	c.93-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC2	ENST00000375363.8	c.441-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021176.3	P1

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 393 AN: 152118 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00908

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000724 AC: 182 AN: 251274 Hom.: 0 AF XY: 0.000515 AC XY: 70 AN XY: 135824

Gnomad AFR exome AF: 0.00972

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000320 AC: 422 AN: 1317992 Hom.: 1 Cov.: 21 AF XY: 0.000268 AC XY: 178 AN XY: 663770

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000640

Gnomad4 SAS exome AF: 0.0000960

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000245

Gnomad4 OTH exome AF: 0.000558

GnomAD4 genome AF: 0.00258 AC: 393 AN: 152236 Hom.: 1 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74404

Gnomad4 AFR AF: 0.00905

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.00286

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

G6PC2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.16
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.030		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: rs181737385; hg19: chr2-169763170;