2-168906660-G-A

Variant names:

• chr2-168906660-G-A
• rs181737385
• NM_021176.3:c.441-4G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_021176.3(G6PC2):​c.441-4G>A variant causes a splice region, 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: G6PC2 NM_021176.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002811
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.126
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -5 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 no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC2	NM_021176.3	c.441-4G>A		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000375363.8	NP_066999.1
G6PC2	NM_001081686.2	c.441-908G>A		intron_variant	Intron 3 of 3		NP_001075155.1
G6PC2	XM_011511564.4	c.329-908G>A		intron_variant	Intron 2 of 2		XP_011509866.1
G6PC2	XM_011511565.4	c.93-4G>A		splice_region_variant, intron_variant	Intron 2 of 3		XP_011509867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC2	ENST00000375363.8	c.441-4G>A		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_021176.3	ENSP00000364512.3

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

GnomAD2 exomes AF: 0.000724 AC: 182 AN: 251274 AF XY: 0.000515

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 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

African (AFR) AF: 0.0106 AC: 325 AN: 30772

American (AMR) AF: 0.000202 AC: 9 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.000640 AC: 25 AN: 39060

South Asian (SAS) AF: 0.0000960 AC: 8 AN: 83304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 0.0000245 AC: 24 AN: 980742

Other (OTH) AF: 0.000558 AC: 31 AN: 55570

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

African (AFR) AF: 0.00905 AC: 376 AN: 41536

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

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: no assertion criteria provided

Submissions by phenotype

G6PC2-related disorder Benign:1

May 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.13
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs181737385; hg19: chr2-169763170;