2-168907638-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_021176.3(G6PC2):c.627G>A(p.Lys209=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,613,948 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (8 hom.)
• Consequence: G6PC2 NM_021176.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.07

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-168907638-G-A is Benign according to our data. Variant chr2-168907638-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3041171.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.07 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC2	NM_021176.3	c.627G>A	p.Lys209=	synonymous_variant	5/5	ENST00000375363.8
G6PC2	XM_011511564.4	c.399G>A	p.Lys133=	synonymous_variant	3/3
G6PC2	XM_011511565.4	c.279G>A	p.Lys93=	synonymous_variant	4/4
G6PC2	NM_001081686.2	c.*46G>A		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC2	ENST00000375363.8	c.627G>A	p.Lys209=	synonymous_variant	5/5	1	NM_021176.3	P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00138 AC: 348 AN: 251446 Hom.: 0 AF XY: 0.00141 AC XY: 191 AN XY: 135894

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00222 AC: 3245 AN: 1461692 Hom.: 8 Cov.: 33 AF XY: 0.00217 AC XY: 1576 AN XY: 727178

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00262

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74442

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00233 Hom.: 0

Bravo AF: 0.00195

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

G6PC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

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	-0.44
Cadd	Benign	13
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs2232324; hg19: chr2-169764148;