chr12-21563244-G-C

Variant names:

• chr12-21563244-G-C
• rs267603422
• NM_021957.4:c.925C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021957.4(GYS2):​c.925C>G​(p.Arg309Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,448,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GYS2 NM_021957.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.32

Genes affected

GYS2 (HGNC:4707): (glycogen synthase 2) The protein encoded by this gene, liver glycogen synthase, catalyzes the rate-limiting step in the synthesis of glycogen - the transfer of a glucose molecule from UDP-glucose to a terminal branch of the glycogen molecule. Mutations in this gene cause glycogen storage disease type 0 (GSD-0) - a rare type of early childhood fasting hypoglycemia with decreased liver glycogen content. [provided by RefSeq, Dec 2009]

ENSG00000285854 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.925C>G	p.Arg309Gly	missense_variant	Exon 6 of 16	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.925C>G	p.Arg309Gly	missense_variant	Exon 6 of 17		XP_024304728.1
GYS2	XM_006719063.4	c.694C>G	p.Arg232Gly	missense_variant	Exon 5 of 15		XP_006719126.1
GYS2	XM_017019245.3	c.925C>G	p.Arg309Gly	missense_variant	Exon 6 of 9		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.925C>G	p.Arg309Gly	missense_variant	Exon 6 of 16	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*927C>G		non_coding_transcript_exon_variant	Exon 13 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000647960.1	n.*927C>G		3_prime_UTR_variant	Exon 13 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.852C>G		non_coding_transcript_exon_variant	Exon 6 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251246 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

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: 1448592 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 721528

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Benign	0.58	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.014	D
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.071	T
Polyphen		0.98	D
Vest4		0.93
MutPred		0.75		Gain of catalytic residue at F312 (P = 2e-04);
MVP		0.90
MPC		0.64
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.75
gMVP		0.88

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: rs267603422; hg19: chr12-21716178;