chr12-21560468-T-C

Variant names:

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

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: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.1087A>G	p.Met363Val	missense_variant	Exon 8 of 16	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1087A>G	p.Met363Val	missense_variant	Exon 8 of 17		XP_024304728.1
GYS2	XM_006719063.4	c.856A>G	p.Met286Val	missense_variant	Exon 7 of 15		XP_006719126.1
GYS2	XM_017019245.3	c.1087A>G	p.Met363Val	missense_variant	Exon 8 of 9		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1087A>G	p.Met363Val	missense_variant	Exon 8 of 16	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*1089A>G		non_coding_transcript_exon_variant	Exon 15 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000647960.1	n.*1089A>G		3_prime_UTR_variant	Exon 15 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.1014A>G		non_coding_transcript_exon_variant	Exon 8 of 11

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

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;