rs138596591

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004130.4(GYG1):c.961C>T(p.Arg321Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

GYG1
NM_004130.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYG1	NM_004130.4 linkuse as main transcript	c.961C>T	p.Arg321Trp	missense_variant	8/8	ENST00000345003.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYG1	ENST00000345003.9 linkuse as main transcript	c.961C>T	p.Arg321Trp	missense_variant	8/8	1	NM_004130.4		P46976-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251308

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461632

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000125

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 07, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 321 of the GYG1 protein (p.Arg321Trp). This variant is present in population databases (rs138596591, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with GYG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 542120). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Pathogenic

0.16

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Uncertain

0.18

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.80

MVP

0.88

MPC

0.16

ClinPred

0.84

GERP RS

2.6

Varity_R

0.65

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over