chr12-21546416-A-G

Variant names:

• chr12-21546416-A-G
• rs539369206
• NM_021957.4:c.1477T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021957.4(GYS2):​c.1477T>C​(p.Tyr493His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. Y493N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GYS2 NM_021957.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.26
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	NM_021957.4	MANE Select	c.1477T>C	p.Tyr493His	missense	Exon 12 of 16	NP_068776.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	ENST00000261195.3	TSL:1 MANE Select	c.1477T>C	p.Tyr493His	missense	Exon 12 of 16	ENSP00000261195.2
	ENSG00000285854	ENST00000647960.1		n.*1479T>C		non_coding_transcript_exon	Exon 19 of 23	ENSP00000497202.1
	ENSG00000285854	ENST00000647960.1		n.*1479T>C		3_prime_UTR	Exon 19 of 23	ENSP00000497202.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.79		Gain of disorder (P = 0.0197)
MVP		0.89
MPC		0.62
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.86
gMVP		0.89
Mutation Taster		=48/52	disease causing

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: rs539369206; hg19: chr12-21699350;