rs868267884

Variant names:

• chr2-168901489-T-C
• rs868267884
• NM_021176.3:c.158T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021176.3(G6PC2):​c.158T>C​(p.Val53Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,447,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: G6PC2 NM_021176.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38427603).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021176.3. 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
	G6PC2	NM_021176.3	MANE Select	c.158T>C	p.Val53Ala	missense	Exon 1 of 5	NP_066999.1	Q9NQR9-1
	G6PC2	NM_001081686.2		c.158T>C	p.Val53Ala	missense	Exon 1 of 4	NP_001075155.1	Q9NQR9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC2	ENST00000375363.8	TSL:1 MANE Select	c.158T>C	p.Val53Ala	missense	Exon 1 of 5	ENSP00000364512.3	Q9NQR9-1
	G6PC2	ENST00000282075.5	TSL:1	n.158T>C		non_coding_transcript_exon	Exon 1 of 4	ENSP00000282075.4	Q9NQR9-2
	G6PC2	ENST00000429379.2	TSL:2	c.158T>C	p.Val53Ala	missense	Exon 1 of 4	ENSP00000396939.2	Q9NQR9-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447070 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 720908

African (AFR) AF: 0.00 AC: 0 AN: 33188

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098652

Other (OTH) AF: 0.0000167 AC: 1 AN: 59898

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.8
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.20	T
Polyphen		0.013	B
Vest4		0.28
MutPred		0.56		Loss of stability (P = 0.0995)
MVP		0.85
MPC		0.17
ClinPred		0.90	D
GERP RS		5.6
PromoterAI		0.00080	Neutral
Varity_R		0.14
gMVP		0.71
Mutation Taster		=76/24	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

Other links and lift over

dbSNP: rs868267884; hg19: chr2-169757999;