GYS1 p.Met416Leu

Variant names:

• chr19-48977986-T-A
• NM_002103.5:c.1246A>T
• GYS1 p.Met416Leu

Your query was ambiguous. Multiple possible variants found:

• chr19-48977986-T-A
• chr19-48977986-T-G
• chr19-48977984-CAT-TAA
• chr19-48977984-CAT-AAG
• chr19-48977984-CAT-GAG
• chr19-48977984-CAT-TAG

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.1246A>T​(p.Met416Leu) 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. M416V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GYS1 NM_002103.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• Publications: 0 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: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

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=0.16384268).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS1	NM_002103.5	MANE Select	c.1246A>T	p.Met416Leu	missense	Exon 10 of 16	NP_002094.2
	GYS1	NM_001161587.2		c.1054A>T	p.Met352Leu	missense	Exon 9 of 15	NP_001155059.1	P13807-2
	GYS1	NR_027763.2		n.1261A>T		non_coding_transcript_exon	Exon 9 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS1	ENST00000323798.8	TSL:1 MANE Select	c.1246A>T	p.Met416Leu	missense	Exon 10 of 16	ENSP00000317904.3	P13807-1
	GYS1	ENST00000263276.6	TSL:1	c.1054A>T	p.Met352Leu	missense	Exon 9 of 15	ENSP00000263276.6	P13807-2
	GYS1	ENST00000960032.1		c.1312A>T	p.Met438Leu	missense	Exon 10 of 16	ENSP00000630091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.25	N
PhyloP100		1.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.43	T
Sift4G	Benign	0.35	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.39
Mutation Taster		=89/11	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-49481243;