rs117474773

Positions:

chr12-21537012-A-G

Variant summary

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

The NM_021957.4(GYS2):c.2054T>C(p.Phe685Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00654 in 1,613,986 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. F685F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0068 ( 29 hom. )

Consequence

GYS2
NM_021957.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.97

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:

LOC124902896 (HGNC:):

LOC124902896 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=0.007264048).

BP6

Variant 12-21537012-A-G is Benign according to our data. Variant chr12-21537012-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 137529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21537012-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00386 (587/152248) while in subpopulation NFE AF= 0.0075 (510/68018). AF 95% confidence interval is 0.00696. There are 2 homozygotes in gnomad4. There are 255 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GYS2	NM_021957.4 linkuse as main transcript	c.2054T>C	p.Phe685Ser	missense_variant	16/16	ENST00000261195.3
LOC124902896	XR_007063240.1 linkuse as main transcript	n.519-34A>G		intron_variant, non_coding_transcript_variant
GYS2	XM_024448960.2 linkuse as main transcript	c.2054T>C	p.Phe685Ser	missense_variant	16/17
GYS2	XM_006719063.4 linkuse as main transcript	c.1823T>C	p.Phe608Ser	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GYS2	ENST00000261195.3 linkuse as main transcript	c.2054T>C	p.Phe685Ser	missense_variant	16/16	1	NM_021957.4	P1
SPX	ENST00000537527.1 linkuse as main transcript	n.472-34A>G		intron_variant, non_coding_transcript_variant		3
SPX	ENST00000649016.1 linkuse as main transcript	n.529-34A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00387

AC:

588

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00750

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00407

AC:

1022

AN:

251170

Hom.:

AF XY:

0.00401

AC XY:

544

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00240

Gnomad NFE exome

AF:

0.00765

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00682

AC:

9962

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00664

AC XY:

4826

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00271

Gnomad4 NFE exome

AF:

0.00835

Gnomad4 OTH exome

AF:

0.00633

GnomAD4 genome

AF:

0.00386

AC:

587

AN:

152248

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

255

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00104

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00750

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00639

Hom.:

Bravo

AF:

0.00381

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00428

AC:

520

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00632

EpiControl

AF:

0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 2012

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

GYS2: BS2 -

GYS2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.074

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

M_CAP

Benign

0.047

MetaRNN

Benign

0.0073

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.97

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.39

REVEL

Benign

0.20

Sift

Uncertain

0.0070

Sift4G

Benign

0.19

Polyphen

0.27

Vest4

0.47

MVP

0.76

MPC

0.38

ClinPred

0.021

GERP RS

5.5

Varity_R

0.24

gMVP

0.30

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