rs4639981

Variant names:

• chr12-21560374-T-A
• rs4639981
• NM_021957.4:c.1169+12A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-21560374-T-A
• chr12-21560374-T-C
• chr12-21560374-T-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.1169+12A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,354,606 control chromosomes in the GnomAD database, including 438,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45053 hom., cov: 32)
  • Exomes 𝑓: 0.81 (393434 hom.)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.657
• Publications: 11 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=-0.89).
• BP6: Variant 12-21560374-T-A is Benign according to our data. Variant chr12-21560374-T-A is described in ClinVar as Benign. ClinVar VariationId is 261463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.1169+12A>T		intron_variant	Intron 8 of 15	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1169+12A>T		intron_variant	Intron 8 of 16		XP_024304728.1
GYS2	XM_006719063.4	c.938+12A>T		intron_variant	Intron 7 of 14		XP_006719126.1
GYS2	XM_017019245.3	c.1169+12A>T		intron_variant	Intron 8 of 8		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1169+12A>T		intron_variant	Intron 8 of 15	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*1171+12A>T		intron_variant	Intron 15 of 22			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.1096+12A>T		intron_variant	Intron 8 of 10

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116592 AN: 152016 Hom.: 45019 Cov.: 32

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.806

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.714

GnomAD2 exomes AF: 0.791 AC: 198817 AN: 251222 AF XY: 0.792

Gnomad AFR exome AF: 0.676

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.738

Gnomad EAS exome AF: 0.749

Gnomad FIN exome AF: 0.822

Gnomad NFE exome AF: 0.807

Gnomad OTH exome AF: 0.761

GnomAD4 exome AF: 0.807 AC: 970991 AN: 1202472 Hom.: 393434 Cov.: 17 AF XY: 0.807 AC XY: 493451 AN XY: 611492

African (AFR) AF: 0.681 AC: 19464 AN: 28602

American (AMR) AF: 0.802 AC: 35642 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 18300 AN: 24610

East Asian (EAS) AF: 0.785 AC: 30208 AN: 38474

South Asian (SAS) AF: 0.803 AC: 64977 AN: 80882

European-Finnish (FIN) AF: 0.820 AC: 43660 AN: 53250

Middle Eastern (MID) AF: 0.677 AC: 3593 AN: 5310

European-Non Finnish (NFE) AF: 0.817 AC: 714796 AN: 875070

Other (OTH) AF: 0.779 AC: 40351 AN: 51830

GnomAD4 genome AF: 0.767 AC: 116683 AN: 152134 Hom.: 45053 Cov.: 32 AF XY: 0.770 AC XY: 57245 AN XY: 74378

African (AFR) AF: 0.683 AC: 28313 AN: 41464

American (AMR) AF: 0.764 AC: 11681 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2563 AN: 3472

East Asian (EAS) AF: 0.752 AC: 3884 AN: 5166

South Asian (SAS) AF: 0.805 AC: 3886 AN: 4830

European-Finnish (FIN) AF: 0.824 AC: 8722 AN: 10590

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55208 AN: 68006

Other (OTH) AF: 0.715 AC: 1511 AN: 2112

Alfa AF: 0.780 Hom.: 8575

Bravo AF: 0.757

Asia WGS AF: 0.759 AC: 2632 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

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

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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. -

not provided Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.8
DANN	Benign	0.57
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4639981; hg19: chr12-21713308; COSMIC: COSV53928596;