12-21559640-C-T

Position:

• chr12-21559640-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000261195.3(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 ENST00000261195.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.85

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 199162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21559640-C-T is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
GYS2	NM_021957.4	c.1229+11G>A		intron_variant		ENST00000261195.3	NP_068776.2
GYS2	XM_006719063.4	c.998+11G>A		intron_variant			XP_006719126.1
GYS2	XM_024448960.2	c.1229+11G>A		intron_variant			XP_024304728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1229+11G>A		intron_variant		1	NM_021957.4	ENSP00000261195	P1

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

GnomAD3 exomes AF: 0.769 AC: 192136 AN: 249736 Hom.: 74249 AF XY: 0.770 AC XY: 103866 AN XY: 134952

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 SAS exome AF: 0.792

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

Gnomad4 AFR exome AF: 0.671

Gnomad4 AMR exome AF: 0.783

Gnomad4 ASJ exome AF: 0.692

Gnomad4 EAS exome AF: 0.784

Gnomad4 SAS exome AF: 0.790

Gnomad4 FIN exome AF: 0.804

Gnomad4 NFE exome AF: 0.784

Gnomad4 OTH exome AF: 0.751

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

Gnomad4 AFR AF: 0.677

Gnomad4 AMR AF: 0.743

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.752

Gnomad4 SAS AF: 0.795

Gnomad4 FIN AF: 0.809

Gnomad4 NFE AF: 0.782

Gnomad4 OTH AF: 0.686

Alfa AF: 0.717 Hom.: 4701

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs1871137; hg19: chr12-21712574;