rs2306180

Variant names:

• chr12-21560468-T-A
• rs2306180
• NM_021957.4:c.1087A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-21560468-T-A
• chr12-21560468-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021957.4(GYS2):​c.1087A>T​(p.Met363Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M363V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GYS2 NM_021957.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80
• Publications: 39 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14529252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.1087A>T	p.Met363Leu	missense_variant	Exon 8 of 16	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1087A>T	p.Met363Leu	missense_variant	Exon 8 of 17		XP_024304728.1
GYS2	XM_006719063.4	c.856A>T	p.Met286Leu	missense_variant	Exon 7 of 15		XP_006719126.1
GYS2	XM_017019245.3	c.1087A>T	p.Met363Leu	missense_variant	Exon 8 of 9		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1087A>T	p.Met363Leu	missense_variant	Exon 8 of 16	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*1089A>T		non_coding_transcript_exon_variant	Exon 15 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000647960.1	n.*1089A>T		3_prime_UTR_variant	Exon 15 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.1014A>T		non_coding_transcript_exon_variant	Exon 8 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424634 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 711148

African (AFR) AF: 0.00 AC: 0 AN: 32750

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.00 AC: 0 AN: 85498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078056

Other (OTH) AF: 0.00 AC: 0 AN: 59110

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.30		Gain of catalytic residue at V364 (P = 2e-04);
MVP		0.27
MPC		0.11
ClinPred		0.60	D
GERP RS		4.0
Varity_R		0.47
gMVP		0.71
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2306180; hg19: chr12-21713402;