rs5461

Variant names:

• chr19-48982813-T-C
• rs5461
• NM_002103.5:c.848A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002103.5(GYS1):​c.848A>G​(p.Asn283Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,734 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GYS1 NM_002103.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.26

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS1	NM_002103.5	c.848A>G	p.Asn283Ser	missense_variant	Exon 6 of 16	ENST00000323798.8	NP_002094.2
GYS1	NM_001161587.2	c.656A>G	p.Asn219Ser	missense_variant	Exon 5 of 15		NP_001155059.1
GYS1	NR_027763.2	n.863A>G		non_coding_transcript_exon_variant	Exon 5 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS1	ENST00000323798.8	c.848A>G	p.Asn283Ser	missense_variant	Exon 6 of 16	1	NM_002103.5	ENSP00000317904.3
GYS1	ENST00000263276.6	c.656A>G	p.Asn219Ser	missense_variant	Exon 5 of 15	1		ENSP00000263276.6
GYS1	ENST00000484289.2	n.39A>G		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458734 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000245 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Uncertain	0.097	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.34	B;.
Vest4		0.53
MutPred		0.29		Gain of ubiquitination at K286 (P = 0.0582);.;
MVP		0.76
MPC		1.2
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5461; hg19: chr19-49486070;