rs4639981

Variant names:

• chr12-21560374-T-A
• rs4639981
• NM_021957.4:c.1169+12A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-21560374-T-A
• chr12-21560374-T-C
• chr12-21560374-T-G

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.1169+12A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,354,606 control chromosomes in the GnomAD database, including 438,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45053 hom., cov: 32)
  • Exomes 𝑓: 0.81 (393434 hom.)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.657
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-21560374-T-A is Benign according to our data. Variant chr12-21560374-T-A is described in ClinVar as Benign. ClinVar VariationId is 261463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.806 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.1169+12A>T		intron	N/A	NP_068776.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	ENST00000261195.3	TSL:1 MANE Select	c.1169+12A>T		intron	N/A	ENSP00000261195.2
	ENSG00000285854	ENST00000647960.1		n.*1171+12A>T		intron	N/A	ENSP00000497202.1
	GYS2	ENST00000863011.1		c.1283+12A>T		intron	N/A	ENSP00000533070.1

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116592 AN: 152016 Hom.: 45019 Cov.: 32

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.806

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.714

GnomAD2 exomes AF: 0.791 AC: 198817 AN: 251222 AF XY: 0.792

Gnomad AFR exome AF: 0.676

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.738

Gnomad EAS exome AF: 0.749

Gnomad FIN exome AF: 0.822

Gnomad NFE exome AF: 0.807

Gnomad OTH exome AF: 0.761

GnomAD4 exome AF: 0.807 AC: 970991 AN: 1202472 Hom.: 393434 Cov.: 17 AF XY: 0.807 AC XY: 493451 AN XY: 611492

African (AFR) AF: 0.681 AC: 19464 AN: 28602

American (AMR) AF: 0.802 AC: 35642 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 18300 AN: 24610

East Asian (EAS) AF: 0.785 AC: 30208 AN: 38474

South Asian (SAS) AF: 0.803 AC: 64977 AN: 80882

European-Finnish (FIN) AF: 0.820 AC: 43660 AN: 53250

Middle Eastern (MID) AF: 0.677 AC: 3593 AN: 5310

European-Non Finnish (NFE) AF: 0.817 AC: 714796 AN: 875070

Other (OTH) AF: 0.779 AC: 40351 AN: 51830

GnomAD4 genome AF: 0.767 AC: 116683 AN: 152134 Hom.: 45053 Cov.: 32 AF XY: 0.770 AC XY: 57245 AN XY: 74378

African (AFR) AF: 0.683 AC: 28313 AN: 41464

American (AMR) AF: 0.764 AC: 11681 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2563 AN: 3472

East Asian (EAS) AF: 0.752 AC: 3884 AN: 5166

South Asian (SAS) AF: 0.805 AC: 3886 AN: 4830

European-Finnish (FIN) AF: 0.824 AC: 8722 AN: 10590

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55208 AN: 68006

Other (OTH) AF: 0.715 AC: 1511 AN: 2112

Alfa AF: 0.780 Hom.: 8575

Bravo AF: 0.757

Asia WGS AF: 0.759 AC: 2632 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.8
DANN	Benign	0.57
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4639981; hg19: chr12-21713308; COSMIC: COSV53928596;