12-21560468-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021957.4(GYS2):c.1087A>G(p.Met363Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 1,572,172 control chromosomes in the GnomAD database, including 482,680 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 42603 hom., cov: 32)

Exomes 𝑓: 0.79 ( 440077 hom. )

Consequence

GYS2
NM_021957.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.80

Variant links:

Genes affected

GYS2 (HGNC:4707): (glycogen synthase 2) The protein encoded by this gene, liver glycogen synthase, catalyzes the rate-limiting step in the synthesis of glycogen - the transfer of a glucose molecule from UDP-glucose to a terminal branch of the glycogen molecule. Mutations in this gene cause glycogen storage disease type 0 (GSD-0) - a rare type of early childhood fasting hypoglycemia with decreased liver glycogen content. [provided by RefSeq, Dec 2009]

GYS2 links:

ENSG00000285854 (HGNC:):

ENSG00000285854 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.3008766E-7).

BP6

Variant 12-21560468-T-C is Benign according to our data. Variant chr12-21560468-T-C is described in ClinVar as [Benign]. Clinvar id is 261462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21560468-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4 link	c.1087A>G	p.Met363Val	missense_variant	Exon 8 of 16	ENST00000261195.3	NP_068776.2	P54840
GYS2	XM_024448960.2 link	c.1087A>G	p.Met363Val	missense_variant	Exon 8 of 17		XP_024304728.1
GYS2	XM_006719063.4 link	c.856A>G	p.Met286Val	missense_variant	Exon 7 of 15		XP_006719126.1
GYS2	XM_017019245.3 link	c.1087A>G	p.Met363Val	missense_variant	Exon 8 of 9		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GYS2	ENST00000261195.3 link	c.1087A>G	p.Met363Val	missense_variant	Exon 8 of 16	1	NM_021957.4	ENSP00000261195.2	P54840
ENSG00000285854	ENST00000647960.1 link	n.*1089A>G		non_coding_transcript_exon_variant	Exon 15 of 23			ENSP00000497202.1	A0A3B3IS95
ENSG00000285854	ENST00000647960.1 link	n.*1089A>G		3_prime_UTR_variant	Exon 15 of 23			ENSP00000497202.1	A0A3B3IS95
ENSG00000285854	ENST00000648372.1 link	n.1014A>G		non_coding_transcript_exon_variant	Exon 8 of 11

Frequencies

GnomAD3 genomes

AF:

0.746

AC:

113390

AN:

151966

Hom.:

42566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.677

Gnomad AMI

AF:

0.631

Gnomad AMR

AF:

0.741

Gnomad ASJ

AF:

0.689

Gnomad EAS

AF:

0.752

Gnomad SAS

AF:

0.797

Gnomad FIN

AF:

0.810

Gnomad MID

AF:

0.604

Gnomad NFE

AF:

0.782

Gnomad OTH

AF:

0.684

GnomAD3 exomes

AF:

0.770

AC:

193463

AN:

251334

Hom.:

74829

AF XY:

0.770

AC XY:

104600

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.670

Gnomad AMR exome

AF:

0.788

Gnomad ASJ exome

AF:

0.690

Gnomad EAS exome

AF:

0.749

Gnomad SAS exome

AF:

0.792

Gnomad FIN exome

AF:

0.807

Gnomad NFE exome

AF:

0.778

Gnomad OTH exome

AF:

0.733

GnomAD4 exome

AF:

0.786

AC:

1115961

AN:

1420088

Hom.:

440077

Cov.:

AF XY:

0.785

AC XY:

556918

AN XY:

709100

show subpopulations

Gnomad4 AFR exome

AF:

0.676

Gnomad4 AMR exome

AF:

0.783

Gnomad4 ASJ exome

AF:

0.694

Gnomad4 EAS exome

AF:

0.784

Gnomad4 SAS exome

AF:

0.792

Gnomad4 FIN exome

AF:

0.804

Gnomad4 NFE exome

AF:

0.793

Gnomad4 OTH exome

AF:

0.756

GnomAD4 genome

AF:

0.746

AC:

113485

AN:

152084

Hom.:

42603

Cov.:

AF XY:

0.749

AC XY:

55721

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.677

Gnomad4 AMR

AF:

0.742

Gnomad4 ASJ

AF:

0.689

Gnomad4 EAS

AF:

0.752

Gnomad4 SAS

AF:

0.795

Gnomad4 FIN

AF:

0.810

Gnomad4 NFE

AF:

0.782

Gnomad4 OTH

AF:

0.686

Alfa

AF:

0.768

Hom.:

84460

Bravo

AF:

0.736

TwinsUK

AF:

0.794

AC:

2945

ALSPAC

AF:

0.792

AC:

3052

ESP6500AA

AF:

0.676

AC:

2980

ESP6500EA

AF:

0.777

AC:

6680

ExAC

AF:

0.768

AC:

93297

Asia WGS

AF:

0.755

AC:

2622

AN:

3478

EpiCase

AF:

0.763

EpiControl

AF:

0.752

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.22

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.59

MetaRNN

Benign

7.3e-7

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-3.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

2.6

REVEL

Benign

0.19

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.081

MPC

0.12

ClinPred

0.0018

GERP RS

4.0

Varity_R

0.059

gMVP

0.55

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