chr12-21574275-G-A

Position:

chr12-21574275-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_021957.4(GYS2):c.547C>T(p.Gln183*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000917 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

GYS2
NM_021957.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.45

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-21574275-G-A is Pathogenic according to our data. Variant chr12-21574275-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 214529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21574275-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYS2	NM_021957.4 linkuse as main transcript	c.547C>T	p.Gln183*	stop_gained	4/16	ENST00000261195.3	NP_068776.2	P54840
GYS2	XM_024448960.2 linkuse as main transcript	c.547C>T	p.Gln183*	stop_gained	4/17		XP_024304728.1
GYS2	XM_006719063.4 linkuse as main transcript	c.316C>T	p.Gln106*	stop_gained	3/15		XP_006719126.1
GYS2	XM_017019245.3 linkuse as main transcript	c.547C>T	p.Gln183*	stop_gained	4/9		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GYS2	ENST00000261195.3 linkuse as main transcript	c.547C>T	p.Gln183*	stop_gained	4/16	1	NM_021957.4	ENSP00000261195.2	P54840
ENSG00000285854	ENST00000647960.1 linkuse as main transcript	n.*549C>T		non_coding_transcript_exon_variant	11/23			ENSP00000497202.1	A0A3B3IS95
ENSG00000285854	ENST00000647960.1 linkuse as main transcript	n.*549C>T		3_prime_UTR_variant	11/23			ENSP00000497202.1	A0A3B3IS95
ENSG00000285854	ENST00000648372.1 linkuse as main transcript	n.474C>T		non_coding_transcript_exon_variant	4/11

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251042

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000944

AC:

138

AN:

1461310

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000833

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). This homozygous variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000214529 / PMID: 12072888). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 26, 2021	This sequence change creates a premature translational stop signal (p.Gln183*) in the GYS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GYS2 are known to be pathogenic (PMID: 9691087). This variant is present in population databases (rs201157731, ExAC 0.02%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type 0 (PMID: 12072888). ClinVar contains an entry for this variant (Variation ID: 214529). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with liver glycogen storage disease 0 (MIM#240600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are reported to have variable clinical phenotypes (PMIDs: 32395408, 28245189, 18341095). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in patients with glycogen storage disease type 0 (ClinVar, PMIDs: 12072888, 32377253). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity and has previously been reported in patients with glycogen storage disease 0 (ClinVar, PMID: 32395408). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant in a recessive disease. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Gln183Ter variant in GYS2 was identified by our study in one individual with hypotonia. The p.Gln183Ter variant in GYS2 has been previously reported in two unrelated individuals with liver glycogen storage disorder 0 but has been identified in 0.01% (9/68028) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201157731). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. These two affected individuals (PMID: 12072888, PMID: 32377253) were compound heterozygous who carried pathogenic or likely pathogenic variants in trans (PMID: 12072888, PMID: 32377253, ClinVar Variation ID: 937499), which increases the likelihood that the p.Gln183Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 214529) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 183, which is predicted to lead to a truncated or absent protein. Loss of function of the GYS2 gene is strongly associated to autosomal recessive liver glycogen storage disorder 0. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive liver glycogen storage disorder 0. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong (Richards 2015). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2014	p.Gln183Stop (CAG>TAG): c.547 C>T in exon 4 of the GYS2 gene (NM_021957.3). The Q183X nonsense mutation in the GYS2 gene has been reported in association with glycogen storage disease, type 0. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in MITONUC-MITOP panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.89

Vest4

0.94

GERP RS

5.3

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