rs35403985

Positions:

• chr12-21546429-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021957.4(GYS2):​c.1464A>G​(p.Leu488Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,588,494 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (143 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (144 hom.)
• Consequence: GYS2 NM_021957.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.364

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]

ENSG00000285854 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-21546429-T-C is Benign according to our data. Variant chr12-21546429-T-C is described in ClinVar as [Benign]. Clinvar id is 137525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.364 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYS2	NM_021957.4	c.1464A>G	p.Leu488Leu	synonymous_variant	12/16	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1464A>G	p.Leu488Leu	synonymous_variant	12/17		XP_024304728.1
GYS2	XM_006719063.4	c.1233A>G	p.Leu411Leu	synonymous_variant	11/15		XP_006719126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1464A>G	p.Leu488Leu	synonymous_variant	12/16	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*1466A>G		non_coding_transcript_exon_variant	19/23			ENSP00000497202.1
ENSG00000285854	ENST00000647960.1	n.*1466A>G		3_prime_UTR_variant	19/23			ENSP00000497202.1

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3569 AN: 151700 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00833

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00675 AC: 1684 AN: 249620 Hom.: 64 AF XY: 0.00510 AC XY: 688 AN XY: 134926

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000231

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00279 AC: 4013 AN: 1436678 Hom.: 144 Cov.: 26 AF XY: 0.00249 AC XY: 1780 AN XY: 716128

Gnomad4 AFR exome AF: 0.0864

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000199

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.00613

GnomAD4 genome AF: 0.0235 AC: 3572 AN: 151816 Hom.: 143 Cov.: 32 AF XY: 0.0227 AC XY: 1687 AN XY: 74204

Gnomad4 AFR AF: 0.0804

Gnomad4 AMR AF: 0.00832

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000339

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0152 Hom.: 33

Bravo AF: 0.0266

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000475

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 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2022	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 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:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 12, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.0
DANN	Benign	0.62

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

Other links and lift over

dbSNP: rs35403985; hg19: chr12-21699363;