12-21543515-A-T

Variant names:

• chr12-21543515-A-T
• rs2054436
• NM_021957.4:c.1550-924T>A

Variant summary

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

The NM_021957.4(GYS2):​c.1550-924T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 151,882 control chromosomes in the GnomAD database, including 22,822 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 0.52 (22822 hom., cov: 31)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700
• Publications: 2 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.715 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.1550-924T>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.1550-924T>A		intron	N/A	ENSP00000261195.2	P54840
	ENSG00000285854	ENST00000647960.1		n.*1552-924T>A		intron	N/A	ENSP00000497202.1	A0A3B3IS95
	GYS2	ENST00000863011.1		c.1664-924T>A		intron	N/A	ENSP00000533070.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79695 AN: 151764 Hom.: 22812 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.735

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.495

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

GnomAD4 genome AF: 0.525 AC: 79728 AN: 151882 Hom.: 22822 Cov.: 31 AF XY: 0.532 AC XY: 39478 AN XY: 74208

African (AFR) AF: 0.287 AC: 11863 AN: 41372

American (AMR) AF: 0.618 AC: 9433 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1901 AN: 3470

East Asian (EAS) AF: 0.735 AC: 3791 AN: 5158

South Asian (SAS) AF: 0.714 AC: 3439 AN: 4816

European-Finnish (FIN) AF: 0.596 AC: 6266 AN: 10512

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41445 AN: 67976

Other (OTH) AF: 0.498 AC: 1049 AN: 2108

Alfa AF: 0.441 Hom.: 1389

Bravo AF: 0.515

Asia WGS AF: 0.670 AC: 2325 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.7
DANN	Benign	0.77
PhyloP100		-0.070
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: rs2054436; hg19: chr12-21696449; COSMIC: COSV53928505;