rs756521075

Variant names:

• chr2-168906692-T-C
• rs756521075
• NM_021176.3:c.469T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021176.3(G6PC2):​c.469T>C​(p.Phe157Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: G6PC2 NM_021176.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.469T>C	p.Phe157Leu	missense	Exon 4 of 5	NP_066999.1	Q9NQR9-1
	G6PC2	NM_001081686.2		c.441-876T>C		intron	N/A	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.469T>C	p.Phe157Leu	missense	Exon 4 of 5	ENSP00000364512.3	Q9NQR9-1
	G6PC2	ENST00000282075.5	TSL:1	n.*50T>C		non_coding_transcript_exon	Exon 3 of 4	ENSP00000282075.4	Q9NQR9-2
	G6PC2	ENST00000282075.5	TSL:1	n.*50T>C		3_prime_UTR	Exon 3 of 4	ENSP00000282075.4	Q9NQR9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251432 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1446510 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 720694

African (AFR) AF: 0.00 AC: 0 AN: 33208

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098064

Other (OTH) AF: 0.00 AC: 0 AN: 59782

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.93
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.49
Sift	Benign	0.036	D
Sift4G	Benign	0.19	T
Polyphen		0.86	P
Vest4		0.73
MutPred		0.58		Loss of sheet (P = 0.0315)
MVP		0.74
MPC		0.048
ClinPred		0.43	T
GERP RS		5.9
Varity_R		0.26
gMVP		0.61
Mutation Taster		=67/33	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: rs756521075; hg19: chr2-169763202;