12-21536999-G-A

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.2067C>T(p.His689=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,613,824 control chromosomes in the GnomAD database, including 290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (141 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (149 hom.)
• Consequence: GYS2 NM_021957.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.876

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-21536999-G-A is Benign according to our data. Variant chr12-21536999-G-A is described in ClinVar as [Benign]. Clinvar id is 137530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.876 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	UniProt
GYS2	NM_021957.4	c.2067C>T	p.His689=	synonymous_variant	16/16	ENST00000261195.3
LOC124902896	XR_007063240.1	n.519-47G>A		intron_variant, non_coding_transcript_variant
GYS2	XM_024448960.2	c.2067C>T	p.His689=	synonymous_variant	16/17
GYS2	XM_006719063.4	c.1836C>T	p.His612=	synonymous_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS2	ENST00000261195.3	c.2067C>T	p.His689=	synonymous_variant	16/16	1	NM_021957.4	P1
SPX	ENST00000537527.1	n.472-47G>A		intron_variant, non_coding_transcript_variant		3
SPX	ENST00000649016.1	n.529-47G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3581 AN: 152026 Hom.: 141 Cov.: 32

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00852

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00686 AC: 1722 AN: 251154 Hom.: 69 AF XY: 0.00522 AC XY: 708 AN XY: 135728

Gnomad AFR exome AF: 0.0853

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00283 AC: 4131 AN: 1461680 Hom.: 149 Cov.: 31 AF XY: 0.00252 AC XY: 1829 AN XY: 727168

Gnomad4 AFR exome AF: 0.0870

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.0156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000193

Gnomad4 OTH exome AF: 0.00611

GnomAD4 genome AF: 0.0236 AC: 3584 AN: 152144 Hom.: 141 Cov.: 32 AF XY: 0.0228 AC XY: 1696 AN XY: 74392

Gnomad4 AFR AF: 0.0803

Gnomad4 AMR AF: 0.00851

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00701 Hom.: 31

Bravo AF: 0.0264

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 08, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Benign:2

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

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.30
Dann	Benign	0.77

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: rs7954038; hg19: chr12-21689933;