rs2306180

Variant names:

• chr12-21560468-T-C
• rs2306180
• NM_021957.4:c.1087A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-21560468-T-C
• chr12-21560468-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021957.4(GYS2):​c.1087A>G​(p.Met363Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 1,572,172 control chromosomes in the GnomAD database, including 482,680 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42603 hom., cov: 32)
  • Exomes 𝑓: 0.79 (440077 hom.)
• Consequence: GYS2 NM_021957.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.80
• Publications: 39 publications found

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]

GYS2 Gene-Disease associations (from GenCC):

• glycogen storage disorder due to hepatic glycogen synthase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp

ENSG00000285854 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.3008766E-7).
• BP6: Variant 12-21560468-T-C is Benign according to our data. Variant chr12-21560468-T-C is described in ClinVar as Benign. ClinVar VariationId is 261462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021957.4. 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
	GYS2	NM_021957.4	MANE Select	c.1087A>G	p.Met363Val	missense	Exon 8 of 16	NP_068776.2	P54840

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	ENST00000261195.3	TSL:1 MANE Select	c.1087A>G	p.Met363Val	missense	Exon 8 of 16	ENSP00000261195.2	P54840
	ENSG00000285854	ENST00000647960.1		n.*1089A>G		non_coding_transcript_exon	Exon 15 of 23	ENSP00000497202.1	A0A3B3IS95
	ENSG00000285854	ENST00000647960.1		n.*1089A>G		3_prime_UTR	Exon 15 of 23	ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113390 AN: 151966 Hom.: 42566 Cov.: 32

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.684

GnomAD2 exomes AF: 0.770 AC: 193463 AN: 251334 AF XY: 0.770

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.788

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.749

Gnomad FIN exome AF: 0.807

Gnomad NFE exome AF: 0.778

Gnomad OTH exome AF: 0.733

GnomAD4 exome AF: 0.786 AC: 1115961 AN: 1420088 Hom.: 440077 Cov.: 27 AF XY: 0.785 AC XY: 556918 AN XY: 709100

African (AFR) AF: 0.676 AC: 22076 AN: 32644

American (AMR) AF: 0.783 AC: 34993 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 17965 AN: 25900

East Asian (EAS) AF: 0.784 AC: 30975 AN: 39488

South Asian (SAS) AF: 0.792 AC: 67620 AN: 85406

European-Finnish (FIN) AF: 0.804 AC: 42904 AN: 53362

Middle Eastern (MID) AF: 0.638 AC: 3632 AN: 5694

European-Non Finnish (NFE) AF: 0.793 AC: 851208 AN: 1073958

Other (OTH) AF: 0.756 AC: 44588 AN: 58952

GnomAD4 genome AF: 0.746 AC: 113485 AN: 152084 Hom.: 42603 Cov.: 32 AF XY: 0.749 AC XY: 55721 AN XY: 74358

African (AFR) AF: 0.677 AC: 28097 AN: 41486

American (AMR) AF: 0.742 AC: 11337 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2387 AN: 3466

East Asian (EAS) AF: 0.752 AC: 3881 AN: 5162

South Asian (SAS) AF: 0.795 AC: 3834 AN: 4822

European-Finnish (FIN) AF: 0.810 AC: 8573 AN: 10588

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53175 AN: 67970

Other (OTH) AF: 0.686 AC: 1448 AN: 2110

Alfa AF: 0.770 Hom.: 161705

Bravo AF: 0.736

TwinsUK AF: 0.794 AC: 2945

ALSPAC AF: 0.792 AC: 3052

ESP6500AA AF: 0.676 AC: 2980

ESP6500EA AF: 0.777 AC: 6680

ExAC AF: 0.768 AC: 93297

Asia WGS AF: 0.755 AC: 2622 AN: 3478

EpiCase AF: 0.763

EpiControl AF: 0.752

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycogen storage disorder due to hepatic glycogen synthase deficiency (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.80
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	7.3e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-3.2	N
PhyloP100		2.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.081
MPC		0.12
ClinPred		0.0018	T
GERP RS		4.0
Varity_R		0.059
gMVP		0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs2306180; hg19: chr12-21713402; COSMIC: COSV53923853;