chr12-21536998-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021957.4(GYS2):​c.2068G>A​(p.Val690Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V690F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GYS2
NM_021957.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.427
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.034432888).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GYS2NM_021957.4 linkuse as main transcriptc.2068G>A p.Val690Ile missense_variant 16/16 ENST00000261195.3
LOC124902896XR_007063240.1 linkuse as main transcriptn.519-48C>T intron_variant, non_coding_transcript_variant
GYS2XM_024448960.2 linkuse as main transcriptc.2068G>A p.Val690Ile missense_variant 16/17
GYS2XM_006719063.4 linkuse as main transcriptc.1837G>A p.Val613Ile missense_variant 15/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GYS2ENST00000261195.3 linkuse as main transcriptc.2068G>A p.Val690Ile missense_variant 16/161 NM_021957.4 P1
SPXENST00000537527.1 linkuse as main transcriptn.472-48C>T intron_variant, non_coding_transcript_variant 3
SPXENST00000649016.1 linkuse as main transcriptn.529-48C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251154
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135738
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:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461674
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727162
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00000532
Hom.:
0
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 19, 2023This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 690 of the GYS2 protein (p.Val690Ile). This variant is present in population databases (rs148461282, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GYS2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
0.13
DANN
Benign
0.75
DEOGEN2
Benign
0.19
T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.50
T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.034
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.46
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.090
N
REVEL
Benign
0.035
Sift
Benign
0.32
T
Sift4G
Benign
0.28
T
Polyphen
0.0
B
Vest4
0.029
MutPred
0.15
Gain of catalytic residue at V690 (P = 0.0126);
MVP
0.40
MPC
0.095
ClinPred
0.026
T
GERP RS
-2.5
Varity_R
0.032
gMVP
0.087

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.

Other links and lift over

dbSNP: rs148461282; hg19: chr12-21689932; API