NM_002103.5:c.1246A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002103.5(GYS1):c.1246A>G(p.Met416Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00969 in 1,613,926 control chromosomes in the GnomAD database, including 426 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 67 hom., cov: 31)

Exomes 𝑓: 0.0092 ( 359 hom. )

Consequence

GYS1
NM_002103.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.35

Publications

23 publications found

Variant links:

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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen

GYS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027920902).

BP6

Variant 19-48977986-T-C is Benign according to our data. Variant chr19-48977986-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 329814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GYS1	NM_002103.5	MANE Select	c.1246A>G	p.Met416Val	missense	Exon 10 of 16	NP_002094.2
GYS1	NM_001161587.2		c.1054A>G	p.Met352Val	missense	Exon 9 of 15	NP_001155059.1	P13807-2
GYS1	NR_027763.2		n.1261A>G		non_coding_transcript_exon	Exon 9 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GYS1	ENST00000323798.8	TSL:1 MANE Select	c.1246A>G	p.Met416Val	missense	Exon 10 of 16	ENSP00000317904.3	P13807-1
GYS1	ENST00000263276.6	TSL:1	c.1054A>G	p.Met352Val	missense	Exon 9 of 15	ENSP00000263276.6	P13807-2
GYS1	ENST00000960032.1		c.1312A>G	p.Met438Val	missense	Exon 10 of 16	ENSP00000630091.1

Frequencies

GnomAD3 genomes

AF:

0.0148

AC:

2253

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.0994

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.0616

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00451

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0190

AC:

4768

AN:

251470

AF XY:

0.0185

show subpopulations

Gnomad AFR exome

AF:

0.0138

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.106

Gnomad FIN exome

AF:

0.0593

Gnomad NFE exome

AF:

0.00468

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.00915

AC:

13378

AN:

1461768

Hom.:

359

Cov.:

AF XY:

0.00948

AC XY:

6891

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0134

AC:

449

AN:

33472

American (AMR)

AF:

0.00228

AC:

102

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00406

AC:

106

AN:

26130

East Asian (EAS)

AF:

0.103

AC:

4089

AN:

39694

South Asian (SAS)

AF:

0.0192

AC:

1658

AN:

86252

European-Finnish (FIN)

AF:

0.0563

AC:

3009

AN:

53412

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00293

AC:

3257

AN:

1111926

Other (OTH)

AF:

0.0111

AC:

669

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

845

1690

2536

3381

4226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0149

AC:

2265

AN:

152158

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1339

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0143

AC:

595

AN:

41528

American (AMR)

AF:

0.00295

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3468

East Asian (EAS)

AF:

0.0997

AC:

513

AN:

5148

South Asian (SAS)

AF:

0.0214

AC:

103

AN:

4824

European-Finnish (FIN)

AF:

0.0616

AC:

653

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00451

AC:

307

AN:

68008

Other (OTH)

AF:

0.0152

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

105

210

316

421

526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00781

Hom.:

Bravo

AF:

0.0107

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.0187

AC:

2274

Asia WGS

AF:

0.0530

AC:

183

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00261

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease due to muscle and heart glycogen synthase deficiency (2)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.34

Eigen

Benign

-0.17

Eigen_PC

Benign

0.0093

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

PhyloP100

1.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.89

REVEL

Benign

0.13

Sift

Benign

0.27

Sift4G

Benign

0.29

Polyphen

0.0040

Vest4

0.055

MPC

0.49

ClinPred

0.0079

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.41

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over