NM_002103.5:c.2071C>G

Variant names:

• chr19-48969431-G-C
• rs5453
• NM_002103.5:c.2071C>G

Variant summary

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

The NM_002103.5(GYS1):​c.2071C>G​(p.Pro691Ala) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GYS1 NM_002103.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51
• Publications: 2 publications found

Genes affected

GYS1 (HGNC:4706): (glycogen synthase 1) The protein encoded by this gene catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of alpha-1,4-glycoside linkages. Mutations in this gene are associated with muscle glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

GYS1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to muscle and heart glycogen synthase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp, Orphanet

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=0.25684416).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002103.5. 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
	GYS1	NM_002103.5	MANE Select	c.2071C>G	p.Pro691Ala	missense	Exon 16 of 16	NP_002094.2
	GYS1	NM_001161587.2		c.1879C>G	p.Pro627Ala	missense	Exon 15 of 15	NP_001155059.1
	GYS1	NR_027763.2		n.2086C>G		non_coding_transcript_exon	Exon 15 of 15

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS1	ENST00000323798.8	TSL:1 MANE Select	c.2071C>G	p.Pro691Ala	missense	Exon 16 of 16	ENSP00000317904.3
	GYS1	ENST00000263276.6	TSL:1	c.1879C>G	p.Pro627Ala	missense	Exon 15 of 15	ENSP00000263276.6
	GYS1	ENST00000960032.1		c.2137C>G	p.Pro713Ala	missense	Exon 16 of 16	ENSP00000630091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.058
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.027	D
Polyphen		0.16	B
Vest4		0.26
MutPred		0.077		Gain of helix (P = 0.0022)
MVP		0.71
MPC		0.53
ClinPred		0.82	D
GERP RS		5.6
Varity_R		0.14
gMVP		0.59
Mutation Taster		=65/35	polymorphism

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: rs5453; hg19: chr19-49472688;