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: 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 (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.

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.1229+11G>A		intron	N/A	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.1229+11G>A		intron	N/A	ENSP00000261195.2	P54840
	ENSG00000285854	ENST00000647960.1		n.*1231+11G>A		intron	N/A	ENSP00000497202.1	A0A3B3IS95
	GYS2	ENST00000863011.1		c.1343+11G>A		intron	N/A	ENSP00000533070.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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;