NM_002103.5:c.1246A>C

Variant names:

• chr19-48977986-T-G
• NM_002103.5:c.1246A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002103.5(GYS1):​c.1246A>C​(p.Met416Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GYS1 NM_002103.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16475159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS1	NM_002103.5	c.1246A>C	p.Met416Leu	missense_variant	Exon 10 of 16	ENST00000323798.8	NP_002094.2
GYS1	NM_001161587.2	c.1054A>C	p.Met352Leu	missense_variant	Exon 9 of 15		NP_001155059.1
GYS1	NR_027763.2	n.1261A>C		non_coding_transcript_exon_variant	Exon 9 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS1	ENST00000323798.8	c.1246A>C	p.Met416Leu	missense_variant	Exon 10 of 16	1	NM_002103.5	ENSP00000317904.3
GYS1	ENST00000263276.6	c.1054A>C	p.Met352Leu	missense_variant	Exon 9 of 15	1		ENSP00000263276.6
GYS1	ENST00000472004.5	n.1A>C		non_coding_transcript_exon_variant	Exon 1 of 4	3
GYS1	ENST00000496048.1	n.153A>C		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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	0.92
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.25	N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.17
Sift	Benign	0.43	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0010	B;.
Vest4		0.16
MutPred		0.50		Loss of disorder (P = 0.1059);.;
MVP		0.61
MPC		0.46
ClinPred		0.65	D
GERP RS		5.2
Varity_R		0.23
gMVP		0.39

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-49481243;