rs117639846

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021957.4(GYS2):c.1965G>C(p.Gln655His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 1,613,808 control chromosomes in the GnomAD database, including 540 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 64 hom., cov: 32)

Exomes 𝑓: 0.023 ( 476 hom. )

Consequence

GYS2
NM_021957.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.165

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:

SPX (HGNC:28139): (spexin hormone) The protein encoded by this gene is a hormone involved in modulation of cardiovascular and renal function. It has also been shown in rats to cause weight loss. Several transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

SPX 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=0.0016090274).

BP6

Variant 12-21537101-C-G is Benign according to our data. Variant chr12-21537101-C-G is described in ClinVar as [Benign]. Clinvar id is 137528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0206 (3129/152252) while in subpopulation NFE AF= 0.0293 (1995/68012). AF 95% confidence interval is 0.0283. There are 64 homozygotes in gnomad4. There are 1488 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4 link	c.1965G>C	p.Gln655His	missense_variant	Exon 16 of 16	ENST00000261195.3	NP_068776.2	P54840
GYS2	XM_024448960.2 link	c.1965G>C	p.Gln655His	missense_variant	Exon 16 of 17		XP_024304728.1
GYS2	XM_006719063.4 link	c.1734G>C	p.Gln578His	missense_variant	Exon 15 of 15		XP_006719126.1
LOC124902896	XR_007063240.1 link	n.574C>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GYS2	ENST00000261195.3 link	c.1965G>C	p.Gln655His	missense_variant	Exon 16 of 16	1	NM_021957.4	ENSP00000261195.2	P54840
ENSG00000285854	ENST00000647960.1 link	n.*1967G>C		non_coding_transcript_exon_variant	Exon 23 of 23			ENSP00000497202.1	A0A3B3IS95
ENSG00000285854	ENST00000647960.1 link	n.*1967G>C		3_prime_UTR_variant	Exon 23 of 23			ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3132

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00567

Gnomad AMI

AF:

0.167

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.0114

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0293

Gnomad OTH

AF:

0.0293

GnomAD3 exomes

AF:

0.0214

AC:

5363

AN:

251182

Hom.:

AF XY:

0.0218

AC XY:

2962

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00634

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.0475

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0119

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.0294

Gnomad OTH exome

AF:

0.0273

GnomAD4 exome

AF:

0.0235

AC:

34323

AN:

1461556

Hom.:

476

Cov.:

AF XY:

0.0237

AC XY:

17209

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00421

Gnomad4 AMR exome

AF:

0.0192

Gnomad4 ASJ exome

AF:

0.0486

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0122

Gnomad4 FIN exome

AF:

0.0129

Gnomad4 NFE exome

AF:

0.0258

Gnomad4 OTH exome

AF:

0.0237

GnomAD4 genome

AF:

0.0206

AC:

3129

AN:

152252

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

1488

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00566

Gnomad4 AMR

AF:

0.0220

Gnomad4 ASJ

AF:

0.0487

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.0114

Gnomad4 NFE

AF:

0.0293

Gnomad4 OTH

AF:

0.0285

Alfa

AF:

0.0306

Hom.:

Bravo

AF:

0.0216

TwinsUK

AF:

0.0275

AC:

102

ALSPAC

AF:

0.0259

AC:

100

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0301

AC:

259

ExAC

AF:

0.0208

AC:

2520

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0352

EpiControl

AF:

0.0364

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 30, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disorder due to hepatic glycogen synthase deficiency

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 26, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

8.7

DANN

Benign

0.70

DEOGEN2

Benign

0.18

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.2

PrimateAI

Benign

0.41

PROVEAN

Benign

1.1

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.027

MutPred

0.39

Gain of catalytic residue at Q650 (P = 0.1987);

MPC

0.11

ClinPred

0.0023

GERP RS

-0.34

Varity_R

0.051

gMVP

0.25

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