12-21575411-T-C

Variant names:

• chr12-21575411-T-C
• rs10505873
• NM_021957.4:c.495+455A>G

Variant summary

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

The NM_021957.4(GYS2):​c.495+455A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.552 in 152,008 control chromosomes in the GnomAD database, including 24,328 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 0.55 (24328 hom., cov: 31)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.55
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.495+455A>G		intron_variant	Intron 3 of 15	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.495+455A>G		intron_variant	Intron 3 of 16		XP_024304728.1
GYS2	XM_006719063.4	c.264+455A>G		intron_variant	Intron 2 of 14		XP_006719126.1
GYS2	XM_017019245.3	c.495+455A>G		intron_variant	Intron 3 of 8		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.495+455A>G		intron_variant	Intron 3 of 15	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*497+455A>G		intron_variant	Intron 10 of 22			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.422+455A>G		intron_variant	Intron 3 of 10

Frequencies

GnomAD3 genomes AF: 0.553 AC: 83927 AN: 151890 Hom.: 24318 Cov.: 31

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.705

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.546

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

GnomAD4 genome AF: 0.552 AC: 83970 AN: 152008 Hom.: 24328 Cov.: 31 AF XY: 0.559 AC XY: 41501 AN XY: 74274

African (AFR) AF: 0.395 AC: 16389 AN: 41448

American (AMR) AF: 0.667 AC: 10198 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1981 AN: 3466

East Asian (EAS) AF: 0.820 AC: 4238 AN: 5170

South Asian (SAS) AF: 0.702 AC: 3383 AN: 4816

European-Finnish (FIN) AF: 0.567 AC: 5979 AN: 10552

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.588 AC: 39943 AN: 67950

Other (OTH) AF: 0.548 AC: 1154 AN: 2106

Alfa AF: 0.502 Hom.: 3080

Bravo AF: 0.553

Asia WGS AF: 0.724 AC: 2514 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.014
DANN	Benign	0.52
PhyloP100		-3.5
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: rs10505873; hg19: chr12-21728345;