12-21536802-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021957.4(GYS2):c.*152C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 645,728 control chromosomes in the GnomAD database, including 108,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (20348 hom., cov: 32)
  • Exomes 𝑓: 0.59 (87865 hom.)
• Consequence: GYS2 NM_021957.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.15

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 (BayesDel_noAF=-0.85).
• BP6: Variant 12-21536802-G-A is Benign according to our data. Variant chr12-21536802-G-A is described in ClinVar as [Benign]. Clinvar id is 307985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYS2	NM_021957.4	c.*152C>T		3_prime_UTR_variant	16/16	ENST00000261195.3
LOC124902896	XR_007063240.1	n.519-244G>A		intron_variant, non_coding_transcript_variant
GYS2	XM_006719063.4	c.*152C>T		3_prime_UTR_variant	15/15
GYS2	XM_024448960.2	c.*42+110C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS2	ENST00000261195.3	c.*152C>T		3_prime_UTR_variant	16/16	1	NM_021957.4	P1
SPX	ENST00000537527.1	n.472-244G>A		intron_variant, non_coding_transcript_variant		3
SPX	ENST00000649016.1	n.529-244G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73439 AN: 151920 Hom.: 20339 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.467

GnomAD4 exome AF: 0.588 AC: 290422 AN: 493690 Hom.: 87865 Cov.: 5 AF XY: 0.592 AC XY: 155704 AN XY: 262802

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.657

Gnomad4 ASJ exome AF: 0.506

Gnomad4 EAS exome AF: 0.782

Gnomad4 SAS exome AF: 0.677

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.577

Gnomad4 OTH exome AF: 0.548

GnomAD4 genome AF: 0.483 AC: 73469 AN: 152038 Hom.: 20348 Cov.: 32 AF XY: 0.491 AC XY: 36495 AN XY: 74306

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.595

Gnomad4 ASJ AF: 0.506

Gnomad4 EAS AF: 0.735

Gnomad4 SAS AF: 0.697

Gnomad4 FIN AF: 0.578

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.470

Alfa AF: 0.557 Hom.: 22662

Bravo AF: 0.471

Asia WGS AF: 0.661 AC: 2291 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	3.3
Dann	Benign	0.22

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: rs936; hg19: chr12-21689736;