rs117639846

chr12-21537101-C-G

Variant summary

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

The NM_021957.4(GYS2):c.1965G>C(p.Gln655His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 1,613,808 control chromosomes in the GnomAD database, including 540 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (64 hom., cov: 32)
  • Exomes 𝑓: 0.023 (476 hom.)
• Consequence: GYS2 NM_021957.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.165

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]

LOC124902896 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016090274).
• BP6: Variant 12-21537101-C-G is Benign according to our data. Variant chr12-21537101-C-G is described in ClinVar as [Benign]. Clinvar id is 137528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0206 (3129/152252) while in subpopulation NFE AF= 0.0293 (1995/68012). AF 95% confidence interval is 0.0283. There are 64 homozygotes in gnomad4. There are 1488 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYS2	NM_021957.4	c.1965G>C	p.Gln655His	missense_variant	16/16	ENST00000261195.3
LOC124902896	XR_007063240.1	n.574C>G		non_coding_transcript_exon_variant	2/2
GYS2	XM_024448960.2	c.1965G>C	p.Gln655His	missense_variant	16/17
GYS2	XM_006719063.4	c.1734G>C	p.Gln578His	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS2	ENST00000261195.3	c.1965G>C	p.Gln655His	missense_variant	16/16	1	NM_021957.4	P1
SPX	ENST00000537527.1	n.527C>G		non_coding_transcript_exon_variant	5/5	3
SPX	ENST00000649016.1	n.584C>G		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3132 AN: 152134 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00567

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0293

GnomAD3 exomes AF: 0.0214 AC: 5363 AN: 251182 Hom.: 96 AF XY: 0.0218 AC XY: 2962 AN XY: 135748

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0184

Gnomad ASJ exome AF: 0.0475

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0119

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0294

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0235 AC: 34323 AN: 1461556 Hom.: 476 Cov.: 31 AF XY: 0.0237 AC XY: 17209 AN XY: 727086

Gnomad4 AFR exome AF: 0.00421

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.0486

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0258

Gnomad4 OTH exome AF: 0.0237

GnomAD4 genome AF: 0.0206 AC: 3129 AN: 152252 Hom.: 64 Cov.: 32 AF XY: 0.0200 AC XY: 1488 AN XY: 74460

Gnomad4 AFR AF: 0.00566

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.0293

Gnomad4 OTH AF: 0.0285

Alfa AF: 0.0306 Hom.: 37

Bravo AF: 0.0216

TwinsUK AF: 0.0275 AC: 102

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0301 AC: 259

ExAC AF: 0.0208 AC: 2520

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0352

EpiControl AF: 0.0364

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Glycogen storage disorder due to hepatic glycogen synthase deficiency Benign:2

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	Invitae	Jan 29, 2024	- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	8.7
Dann	Benign	0.70
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	0.90	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.027
MutPred		0.39		Gain of catalytic residue at Q650 (P = 0.1987);
MPC		0.11
ClinPred		0.0023	T
GERP RS		-0.34
Varity_R		0.051
gMVP		0.25

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: rs117639846; hg19: chr12-21690035;