12-21563807-A-G

Variant names:

• chr12-21563807-A-G
• rs10770836
• NM_021957.4:c.824-462T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021957.4(GYS2):​c.824-462T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.728 in 152,012 control chromosomes in the GnomAD database, including 40,561 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (40561 hom., cov: 31)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.771 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.824-462T>C		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.824-462T>C		intron	N/A	ENSP00000261195.2	P54840
	ENSG00000285854	ENST00000647960.1		n.*826-462T>C		intron	N/A	ENSP00000497202.1	A0A3B3IS95
	GYS2	ENST00000863011.1		c.938-462T>C		intron	N/A	ENSP00000533070.1

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110631 AN: 151894 Hom.: 40526 Cov.: 31

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.669

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.728 AC: 110723 AN: 152012 Hom.: 40561 Cov.: 31 AF XY: 0.733 AC XY: 54472 AN XY: 74300

African (AFR) AF: 0.665 AC: 27540 AN: 41432

American (AMR) AF: 0.728 AC: 11108 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2371 AN: 3472

East Asian (EAS) AF: 0.752 AC: 3883 AN: 5164

South Asian (SAS) AF: 0.792 AC: 3816 AN: 4820

European-Finnish (FIN) AF: 0.791 AC: 8361 AN: 10566

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.757 AC: 51485 AN: 67986

Other (OTH) AF: 0.671 AC: 1418 AN: 2112

Alfa AF: 0.742 Hom.: 7107

Bravo AF: 0.719

Asia WGS AF: 0.752 AC: 2611 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.50
PhyloP100		0.0020
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: rs10770836; hg19: chr12-21716741;