2-168907710-G-A

Variant names:

• chr2-168907710-G-A
• rs144077223
• NM_021176.3:c.699G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_021176.3(G6PC2):​c.699G>A​(p.Leu233Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,614,102 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: G6PC2 NM_021176.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.233

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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-168907710-G-A is Benign according to our data. Variant chr2-168907710-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3041913.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.233 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PC2	NM_021176.3	c.699G>A	p.Leu233Leu	synonymous_variant	Exon 5 of 5	ENST00000375363.8	NP_066999.1
G6PC2	XM_011511564.4	c.471G>A	p.Leu157Leu	synonymous_variant	Exon 3 of 3		XP_011509866.1
G6PC2	XM_011511565.4	c.351G>A	p.Leu117Leu	synonymous_variant	Exon 4 of 4		XP_011509867.1
G6PC2	NM_001081686.2	c.*118G>A		3_prime_UTR_variant	Exon 4 of 4		NP_001075155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PC2	ENST00000375363.8	c.699G>A	p.Leu233Leu	synonymous_variant	Exon 5 of 5	1	NM_021176.3	ENSP00000364512.3

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00117 AC: 293 AN: 251486 AF XY: 0.00129

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00159 AC: 2319 AN: 1461860 Hom.: 2 Cov.: 33 AF XY: 0.00153 AC XY: 1113 AN XY: 727232

Gnomad4 AFR exome AF: 0.000508 AC: 17 AN: 33478

Gnomad4 AMR exome AF: 0.000358 AC: 16 AN: 44724

Gnomad4 ASJ exome AF: 0.0000765 AC: 2 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.000243 AC: 21 AN: 86258

Gnomad4 FIN exome AF: 0.000356 AC: 19 AN: 53420

Gnomad4 NFE exome AF: 0.00195 AC: 2168 AN: 1111982

Gnomad4 Remaining exome AF: 0.00111 AC: 67 AN: 60394

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74436

Gnomad4 AFR AF: 0.000409 AC: 0.000409165 AN: 0.000409165

Gnomad4 AMR AF: 0.000327 AC: 0.000326755 AN: 0.000326755

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.000207814 AN: 0.000207814

Gnomad4 FIN AF: 0.0000943 AC: 0.0000942507 AN: 0.0000942507

Gnomad4 NFE AF: 0.00259 AC: 0.00258816 AN: 0.00258816

Gnomad4 OTH AF: 0.000946 AC: 0.000946074 AN: 0.000946074

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00121

EpiCase AF: 0.00234

EpiControl AF: 0.00314

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

G6PC2-related disorder Benign:1

Apr 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.51
CADD	Benign	3.4
DANN	Benign	0.78
Mutation Taster		=99/1	polymorphism

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: rs144077223; hg19: chr2-169764220; COSMIC: COSV56371693;