NM_004130.4:c.304G>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PP5_Very_StrongBS1_SupportingBS2

The NM_004130.4(GYG1):c.304G>C(p.Asp102His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,688 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 2 hom. )

Consequence

GYG1
NM_004130.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16U:3

Conservation

PhyloP100: 9.57

Publications

17 publications found

Variant links:

Genes affected

GYG1 (HGNC:4699): (glycogenin 1) This gene encodes a member of the glycogenin family. Glycogenin is a glycosyltransferase that catalyzes the formation of a short glucose polymer from uridine diphosphate glucose in an autoglucosylation reaction. This reaction is followed by elongation and branching of the polymer, catalyzed by glycogen synthase and branching enzyme, to form glycogen. This gene is expressed in muscle and other tissues. Mutations in this gene result in glycogen storage disease XV. This gene has pseudogenes on chromosomes 1, 8 and 13 respectively. Alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]

GYG1 Gene-Disease associations (from GenCC):

polyglucosan body myopathy type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics
glycogen storage disease XV
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

GYG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP5

Variant 3-148996462-G-C is Pathogenic according to our data. Variant chr3-148996462-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00106 (161/152300) while in subpopulation AMR AF = 0.00203 (31/15296). AF 95% confidence interval is 0.00147. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004130.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GYG1	NM_004130.4	MANE Select	c.304G>C	p.Asp102His	missense	Exon 3 of 8	NP_004121.2
GYG1	NM_001184720.2		c.304G>C	p.Asp102His	missense	Exon 3 of 7	NP_001171649.1	P46976-2
GYG1	NM_001184721.2		c.304G>C	p.Asp102His	missense	Exon 3 of 6	NP_001171650.1	P46976-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GYG1	ENST00000345003.9	TSL:1 MANE Select	c.304G>C	p.Asp102His	missense	Exon 3 of 8	ENSP00000340736.4	P46976-1
GYG1	ENST00000296048.10	TSL:1	c.304G>C	p.Asp102His	missense	Exon 3 of 7	ENSP00000296048.6	P46976-2
GYG1	ENST00000484197.5	TSL:1	c.304G>C	p.Asp102His	missense	Exon 3 of 6	ENSP00000420683.1	P46976-3

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00102

AC:

257

AN:

251340

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00181

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.00191

AC:

2787

AN:

1461388

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

1368

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33468

American (AMR)

AF:

0.00130

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000938

AC:

AN:

53278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00237

AC:

2634

AN:

1111704

Other (OTH)

AF:

0.00131

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

131

261

392

522

653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00106

AC:

161

AN:

152300

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41554

American (AMR)

AF:

0.00203

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00171

AC:

116

AN:

68026

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00154

Hom.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000914

AC:

111

EpiCase

AF:

0.00207

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Polyglucosan body myopathy type 2 (5)

Glycogen storage disease XV (2)

Glycogen storage disease XV;C4015452:Polyglucosan body myopathy type 2 (2)

Acute rhabdomyolysis (1)

Glycogen storage disease (1)

GYG1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.58

MetaRNN

Uncertain

0.61

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

PhyloP100

9.6

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

1.0

MPC

0.56

ClinPred

0.89

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.88

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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