NM_002103.5:c.420A>G

Variant names:

• chr19-48987266-T-C
• rs5458
• NM_002103.5:c.420A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002103.5(GYS1):​c.420A>G​(p.Gly140Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,178 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (59 hom.)
• Consequence: GYS1 NM_002103.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.201
• Publications: 3 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-48987266-T-C is Benign according to our data. Variant chr19-48987266-T-C is described in ClinVar as Benign. ClinVar VariationId is 329824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.201 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0121 (1838/152208) while in subpopulation AFR AF = 0.0367 (1524/41518). AF 95% confidence interval is 0.0352. There are 30 homozygotes in GnomAd4. There are 835 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

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.420A>G	p.Gly140Gly	synonymous	Exon 3 of 16	NP_002094.2
	GYS1	NM_001161587.2		c.301-1231A>G		intron	N/A	NP_001155059.1	P13807-2
	GYS1	NR_027763.2		n.435A>G		non_coding_transcript_exon	Exon 2 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS1	ENST00000323798.8	TSL:1 MANE Select	c.420A>G	p.Gly140Gly	synonymous	Exon 3 of 16	ENSP00000317904.3	P13807-1
	GYS1	ENST00000263276.6	TSL:1	c.301-1231A>G		intron	N/A	ENSP00000263276.6	P13807-2
	GYS1	ENST00000960032.1		c.420A>G	p.Gly140Gly	synonymous	Exon 3 of 16	ENSP00000630091.1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1832 AN: 152090 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00487 AC: 1211 AN: 248812 AF XY: 0.00395

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.00337

Gnomad ASJ exome AF: 0.0338

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000826

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00230 AC: 3359 AN: 1460970 Hom.: 59 Cov.: 31 AF XY: 0.00215 AC XY: 1565 AN XY: 726654

African (AFR) AF: 0.0403 AC: 1349 AN: 33468

American (AMR) AF: 0.00332 AC: 148 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0333 AC: 869 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000931 AC: 8 AN: 85972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000535 AC: 595 AN: 1111610

Other (OTH) AF: 0.00610 AC: 368 AN: 60366

GnomAD4 genome AF: 0.0121 AC: 1838 AN: 152208 Hom.: 30 Cov.: 32 AF XY: 0.0112 AC XY: 835 AN XY: 74428

African (AFR) AF: 0.0367 AC: 1524 AN: 41518

American (AMR) AF: 0.00628 AC: 96 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 131 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68004

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00777 Hom.: 15

Bravo AF: 0.0143

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease due to muscle and heart glycogen synthase deficiency (3)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.52
PhyloP100		-0.20
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs5458; hg19: chr19-49490523;