12-21559640-C-T

Variant names:

• chr12-21559640-C-T
• rs1871137
• NM_021957.4:c.1229+11G>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.1229+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 1,431,098 control chromosomes in the GnomAD database, including 432,041 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42614 hom., cov: 33)
  • Exomes 𝑓: 0.78 (389427 hom.)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.85
• Publications: 10 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 (BayesDel_noAF=-0.79).
• BP6: Variant 12-21559640-C-T is Benign according to our data. Variant chr12-21559640-C-T is described in ClinVar as Benign. ClinVar VariationId is 199162.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.1229+11G>A		intron_variant	Intron 9 of 15	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1229+11G>A		intron_variant	Intron 9 of 16		XP_024304728.1
GYS2	XM_006719063.4	c.998+11G>A		intron_variant	Intron 8 of 14		XP_006719126.1
GYS2	XM_017019245.3	c.*579G>A		downstream_gene_variant			XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1229+11G>A		intron_variant	Intron 9 of 15	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*1231+11G>A		intron_variant	Intron 16 of 22			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.1156+11G>A		intron_variant	Intron 9 of 10

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113426 AN: 152018 Hom.: 42577 Cov.: 33

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.685

GnomAD2 exomes AF: 0.769 AC: 192136 AN: 249736 AF XY: 0.770

Gnomad AFR exome AF: 0.669

Gnomad AMR exome AF: 0.787

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.749

Gnomad FIN exome AF: 0.807

Gnomad NFE exome AF: 0.777

Gnomad OTH exome AF: 0.733

GnomAD4 exome AF: 0.779 AC: 996302 AN: 1278962 Hom.: 389427 Cov.: 20 AF XY: 0.779 AC XY: 503402 AN XY: 645972

African (AFR) AF: 0.671 AC: 20262 AN: 30218

American (AMR) AF: 0.783 AC: 34775 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 17311 AN: 25026

East Asian (EAS) AF: 0.784 AC: 30335 AN: 38694

South Asian (SAS) AF: 0.790 AC: 65243 AN: 82562

European-Finnish (FIN) AF: 0.804 AC: 42839 AN: 53274

Middle Eastern (MID) AF: 0.636 AC: 3450 AN: 5428

European-Non Finnish (NFE) AF: 0.784 AC: 741251 AN: 944970

Other (OTH) AF: 0.751 AC: 40836 AN: 54370

GnomAD4 genome AF: 0.746 AC: 113521 AN: 152136 Hom.: 42614 Cov.: 33 AF XY: 0.749 AC XY: 55727 AN XY: 74374

African (AFR) AF: 0.677 AC: 28102 AN: 41502

American (AMR) AF: 0.743 AC: 11345 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2390 AN: 3472

East Asian (EAS) AF: 0.752 AC: 3890 AN: 5172

South Asian (SAS) AF: 0.795 AC: 3835 AN: 4822

European-Finnish (FIN) AF: 0.809 AC: 8575 AN: 10598

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

European-Non Finnish (NFE) AF: 0.782 AC: 53180 AN: 67978

Other (OTH) AF: 0.686 AC: 1447 AN: 2108

Alfa AF: 0.715 Hom.: 4880

Bravo AF: 0.736

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 30, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disorder due to hepatic glycogen synthase deficiency Benign:3

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.51
PhyloP100		-1.9
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: rs1871137; hg19: chr12-21712574;