dbSNP rs2270938: GYS1:c.1646-61T>A (chr19-48970770-A-T) – ACMG Classification: Benign (-20 pts)

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.1646-61T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,534,400 control chromosomes in the GnomAD database, including 112,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11944 hom., cov: 30)

Exomes 𝑓: 0.38 ( 100753 hom. )

Consequence

GYS1
NM_002103.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0610

Publications

10 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, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

GYS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002103.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 19-48970770-A-T is Benign according to our data. Variant chr19-48970770-A-T is described in ClinVar as Benign. ClinVar VariationId is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 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	Effect	Exon Rank	Protein	UniProt
GYS1	NM_002103.5	MANE Select	c.1646-61T>A	intron	N/A	NP_002094.2
GYS1	NM_001161587.2		c.1454-61T>A	intron	N/A	NP_001155059.1	P13807-2
GYS1	NR_027763.2		n.1661-61T>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GYS1	ENST00000323798.8	TSL:1 MANE Select	c.1646-61T>A	intron	N/A	ENSP00000317904.3	P13807-1
GYS1	ENST00000263276.6	TSL:1	c.1454-61T>A	intron	N/A	ENSP00000263276.6	P13807-2
GYS1	ENST00000960032.1		c.1712-61T>A	intron	N/A	ENSP00000630091.1

Frequencies

GnomAD3 genomes

AF:

0.395

AC:

59799

AN:

151462

Hom.:

11926

Cov.:

show subpopulations

Gnomad AFR

AF:

0.450

Gnomad AMI

AF:

0.375

Gnomad AMR

AF:

0.338

Gnomad ASJ

AF:

0.457

Gnomad EAS

AF:

0.373

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.385

Gnomad OTH

AF:

0.397

GnomAD4 exome

AF:

0.380

AC:

525635

AN:

1382820

Hom.:

100753

Cov.:

AF XY:

0.380

AC XY:

262614

AN XY:

691684

show subpopulations

African (AFR)

AF:

0.455

AC:

14522

AN:

31950

American (AMR)

AF:

0.330

AC:

14506

AN:

43956

Ashkenazi Jewish (ASJ)

AF:

0.463

AC:

11870

AN:

25630

East Asian (EAS)

AF:

0.384

AC:

15024

AN:

39166

South Asian (SAS)

AF:

0.324

AC:

27233

AN:

84022

European-Finnish (FIN)

AF:

0.348

AC:

18373

AN:

52748

Middle Eastern (MID)

AF:

0.463

AC:

2362

AN:

5104

European-Non Finnish (NFE)

AF:

0.383

AC:

399659

AN:

1042678

Other (OTH)

AF:

0.384

AC:

22086

AN:

57566

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

16190

32381

48571

64762

80952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12206

24412

36618

48824

61030

<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:

0.395

AC:

59862

AN:

151580

Hom.:

11944

Cov.:

AF XY:

0.390

AC XY:

28904

AN XY:

74056

show subpopulations

African (AFR)

AF:

0.451

AC:

18592

AN:

41262

American (AMR)

AF:

0.338

AC:

5144

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.457

AC:

1588

AN:

3472

East Asian (EAS)

AF:

0.373

AC:

1915

AN:

5128

South Asian (SAS)

AF:

0.311

AC:

1493

AN:

4798

European-Finnish (FIN)

AF:

0.351

AC:

3688

AN:

10514

Middle Eastern (MID)

AF:

0.479

AC:

140

AN:

292

European-Non Finnish (NFE)

AF:

0.385

AC:

26116

AN:

67864

Other (OTH)

AF:

0.402

AC:

846

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1795

3590

5386

7181

8976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.386

Hom.:

1359

Bravo

AF:

0.397

Asia WGS

AF:

0.301

AC:

1049

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.8

(source)

DANN

Benign

0.93

PhyloP100

-0.061

PromoterAI

0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

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

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