12-21536948-T-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.*6A>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 0.391 in 1,580,222 control chromosomes in the GnomAD database, including 126,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9369 hom., cov: 32)
  • Exomes 𝑓: 0.40 (117383 hom.)
• Consequence: GYS2 NM_021957.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0150

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=-0.68).
• BP6: Variant 12-21536948-T-A is Benign according to our data. Variant chr12-21536948-T-A is described in ClinVar as [Benign]. Clinvar id is 261460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21536948-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYS2	NM_021957.4	c.*6A>T		3_prime_UTR_variant	16/16	ENST00000261195.3
LOC124902896	XR_007063240.1	n.519-98T>A		intron_variant, non_coding_transcript_variant
GYS2	XM_006719063.4	c.*6A>T		3_prime_UTR_variant	15/15
GYS2	XM_024448960.2	c.*6A>T		3_prime_UTR_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS2	ENST00000261195.3	c.*6A>T		3_prime_UTR_variant	16/16	1	NM_021957.4	P1
SPX	ENST00000537527.1	n.472-98T>A		intron_variant, non_coding_transcript_variant		3
SPX	ENST00000649016.1	n.529-98T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48646 AN: 151970 Hom.: 9375 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.415 AC: 104032 AN: 250832 Hom.: 23568 AF XY: 0.418 AC XY: 56646 AN XY: 135560

Gnomad AFR exome AF: 0.0919

Gnomad AMR exome AF: 0.579

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.509

Gnomad SAS exome AF: 0.524

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.396

GnomAD4 exome AF: 0.398 AC: 568520 AN: 1428134 Hom.: 117383 Cov.: 26 AF XY: 0.401 AC XY: 285734 AN XY: 712528

Gnomad4 AFR exome AF: 0.0884

Gnomad4 AMR exome AF: 0.573

Gnomad4 ASJ exome AF: 0.368

Gnomad4 EAS exome AF: 0.528

Gnomad4 SAS exome AF: 0.522

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.389

Gnomad4 OTH exome AF: 0.387

GnomAD4 genome AF: 0.320 AC: 48649 AN: 152088 Hom.: 9369 Cov.: 32 AF XY: 0.327 AC XY: 24316 AN XY: 74354

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.502

Gnomad4 SAS AF: 0.532

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.344

Alfa AF: 0.360 Hom.: 3484

Bravo AF: 0.318

Asia WGS AF: 0.501 AC: 1737 AN: 3478

EpiCase AF: 0.376

EpiControl AF: 0.366

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	2.4
Dann	Benign	0.82

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: rs10431213; hg19: chr12-21689882;