rs5447

Variant names:

• chr19-48977986-T-C
• rs5447
• NM_002103.5:c.1246A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-48977986-T-C
• chr19-48977986-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.35
• Publications: 23 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS1	NM_002103.5	c.1246A>G	p.Met416Val	missense_variant	Exon 10 of 16	ENST00000323798.8	NP_002094.2
GYS1	NM_001161587.2	c.1054A>G	p.Met352Val	missense_variant	Exon 9 of 15		NP_001155059.1
GYS1	NR_027763.2	n.1261A>G		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>G	p.Met416Val	missense_variant	Exon 10 of 16	1	NM_002103.5	ENSP00000317904.3
GYS1	ENST00000263276.6	c.1054A>G	p.Met352Val	missense_variant	Exon 9 of 15	1		ENSP00000263276.6
GYS1	ENST00000472004.5	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 4	3
GYS1	ENST00000496048.1	n.153A>G		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2253 AN: 152040 Hom.: 66 Cov.: 31

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

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.: 31 AF XY: 0.00948 AC XY: 6891 AN XY: 727190

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: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.00293 AC: 3257 AN: 1111926

Other (OTH) AF: 0.0111 AC: 669 AN: 60392

GnomAD4 genome AF: 0.0149 AC: 2265 AN: 152158 Hom.: 67 Cov.: 31 AF XY: 0.0180 AC XY: 1339 AN XY: 74376

African (AFR) AF: 0.0143 AC: 595 AN: 41528

American (AMR) AF: 0.00295 AC: 45 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 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: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00451 AC: 307 AN: 68008

Other (OTH) AF: 0.0152 AC: 32 AN: 2110

Alfa AF: 0.00781 Hom.: 96

Bravo AF: 0.0107

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.0187 AC: 2274

Asia WGS AF: 0.0530 AC: 183 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 17, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 06, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Glycogen storage disease due to muscle and heart glycogen synthase deficiency Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0093
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;.
PhyloP100		1.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.13
Sift	Benign	0.27	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0040	B;.
Vest4		0.055
MPC		0.49
ClinPred		0.0079	T
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)

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: rs5447; hg19: chr19-49481243;