rs61733199

Positions:

• chr12-21542505-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000261195.3(GYS2):​c.1636A>G​(p.Thr546Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 1,605,770 control chromosomes in the GnomAD database, including 312 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T546T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 32)
  • Exomes 𝑓: 0.018 (290 hom.)
• Consequence: GYS2 ENST00000261195.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.595

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037274063).
• BP6: Variant 12-21542505-T-C is Benign according to our data. Variant chr12-21542505-T-C is described in ClinVar as [Benign]. Clinvar id is 137526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21542505-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0144 (2199/152346) while in subpopulation NFE AF= 0.019 (1295/68022). AF 95% confidence interval is 0.0182. There are 22 homozygotes in gnomad4. There are 1173 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYS2	NM_021957.4	c.1636A>G	p.Thr546Ala	missense_variant	13/16	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1636A>G	p.Thr546Ala	missense_variant	13/17		XP_024304728.1
GYS2	XM_006719063.4	c.1405A>G	p.Thr469Ala	missense_variant	12/15		XP_006719126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1636A>G	p.Thr546Ala	missense_variant	13/16	1	NM_021957.4	ENSP00000261195	P1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2199 AN: 152228 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0454

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0160 AC: 4020 AN: 251344 Hom.: 59 AF XY: 0.0161 AC XY: 2182 AN XY: 135842

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00928

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0176 AC: 25533 AN: 1453424 Hom.: 290 Cov.: 29 AF XY: 0.0170 AC XY: 12335 AN XY: 723628

Gnomad4 AFR exome AF: 0.00255

Gnomad4 AMR exome AF: 0.00919

Gnomad4 ASJ exome AF: 0.0197

Gnomad4 EAS exome AF: 0.00202

Gnomad4 SAS exome AF: 0.00333

Gnomad4 FIN exome AF: 0.0462

Gnomad4 NFE exome AF: 0.0188

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0144 AC: 2199 AN: 152346 Hom.: 22 Cov.: 32 AF XY: 0.0157 AC XY: 1173 AN XY: 74506

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00980

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0454

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0176 Hom.: 49

Bravo AF: 0.0120

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0206 AC: 177

ExAC AF: 0.0150 AC: 1818

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0153

EpiControl AF: 0.0154

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 07, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.023
Sift	Benign	0.38	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.066
MPC		0.12
ClinPred		0.0020	T
GERP RS		0.30
Varity_R		0.068
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs61733199; hg19: chr12-21695439;