rs4639981

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021957.4(GYS2):​c.1169+12A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,354,606 control chromosomes in the GnomAD database, including 438,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45053 hom., cov: 32)
Exomes 𝑓: 0.81 ( 393434 hom. )

Consequence

GYS2
NM_021957.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.657
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]

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 (BayesDel_noAF=-0.89).
BP6
Variant 12-21560374-T-A is Benign according to our data. Variant chr12-21560374-T-A is described in ClinVar as [Benign]. Clinvar id is 261463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21560374-T-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GYS2NM_021957.4 linkuse as main transcriptc.1169+12A>T intron_variant ENST00000261195.3
GYS2XM_006719063.4 linkuse as main transcriptc.938+12A>T intron_variant
GYS2XM_017019245.3 linkuse as main transcriptc.1169+12A>T intron_variant
GYS2XM_024448960.2 linkuse as main transcriptc.1169+12A>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GYS2ENST00000261195.3 linkuse as main transcriptc.1169+12A>T intron_variant 1 NM_021957.4 P1

Frequencies

GnomAD3 genomes
AF:
0.767
AC:
116592
AN:
152016
Hom.:
45019
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.683
Gnomad AMI
AF:
0.799
Gnomad AMR
AF:
0.763
Gnomad ASJ
AF:
0.738
Gnomad EAS
AF:
0.752
Gnomad SAS
AF:
0.806
Gnomad FIN
AF:
0.824
Gnomad MID
AF:
0.636
Gnomad NFE
AF:
0.812
Gnomad OTH
AF:
0.714
GnomAD3 exomes
AF:
0.791
AC:
198817
AN:
251222
Hom.:
79037
AF XY:
0.792
AC XY:
107564
AN XY:
135780
show subpopulations
Gnomad AFR exome
AF:
0.676
Gnomad AMR exome
AF:
0.806
Gnomad ASJ exome
AF:
0.738
Gnomad EAS exome
AF:
0.749
Gnomad SAS exome
AF:
0.804
Gnomad FIN exome
AF:
0.822
Gnomad NFE exome
AF:
0.807
Gnomad OTH exome
AF:
0.761
GnomAD4 exome
AF:
0.807
AC:
970991
AN:
1202472
Hom.:
393434
Cov.:
17
AF XY:
0.807
AC XY:
493451
AN XY:
611492
show subpopulations
Gnomad4 AFR exome
AF:
0.681
Gnomad4 AMR exome
AF:
0.802
Gnomad4 ASJ exome
AF:
0.744
Gnomad4 EAS exome
AF:
0.785
Gnomad4 SAS exome
AF:
0.803
Gnomad4 FIN exome
AF:
0.820
Gnomad4 NFE exome
AF:
0.817
Gnomad4 OTH exome
AF:
0.779
GnomAD4 genome
AF:
0.767
AC:
116683
AN:
152134
Hom.:
45053
Cov.:
32
AF XY:
0.770
AC XY:
57245
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.683
Gnomad4 AMR
AF:
0.764
Gnomad4 ASJ
AF:
0.738
Gnomad4 EAS
AF:
0.752
Gnomad4 SAS
AF:
0.805
Gnomad4 FIN
AF:
0.824
Gnomad4 NFE
AF:
0.812
Gnomad4 OTH
AF:
0.715
Alfa
AF:
0.780
Hom.:
8575
Bravo
AF:
0.757
Asia WGS
AF:
0.759
AC:
2632
AN:
3476

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Glycogen storage disorder due to hepatic glycogen synthase deficiency Benign:3
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingInvitaeFeb 01, 2024- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicOct 23, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
2.8
DANN
Benign
0.57

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4639981; hg19: chr12-21713308; COSMIC: COSV53928596; API