rs562024109

Variant names:

• chr12-21536409-C-T
• rs562024109
• NM_021957.4:c.*545G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_021957.4(GYS2):​c.*545G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 152,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GYS2 NM_021957.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.214
• Publications: 0 publications found

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]

ENSG00000285854 (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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000184 (28/152218) while in subpopulation SAS AF = 0.00581 (28/4822). AF 95% confidence interval is 0.00413. There are 1 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021957.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	NM_021957.4	MANE Select	c.*545G>A		3_prime_UTR	Exon 16 of 16	NP_068776.2	P54840

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	ENST00000261195.3	TSL:1 MANE Select	c.*545G>A		3_prime_UTR	Exon 16 of 16	ENSP00000261195.2	P54840
	ENSG00000285854	ENST00000647960.1		n.*2659G>A		non_coding_transcript_exon	Exon 23 of 23	ENSP00000497202.1	A0A3B3IS95
	ENSG00000285854	ENST00000647960.1		n.*2659G>A		3_prime_UTR	Exon 23 of 23	ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 7784 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4096

African (AFR) AF: 0.00 AC: 0 AN: 36

American (AMR) AF: 0.00 AC: 0 AN: 1196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 74

East Asian (EAS) AF: 0.00 AC: 0 AN: 290

South Asian (SAS) AF: 0.00 AC: 0 AN: 654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4988

Other (OTH) AF: 0.00 AC: 0 AN: 372

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152218 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74426

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00581 AC: 28 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glycogen storage disorder due to hepatic glycogen synthase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.51
DANN	Benign	0.35
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs562024109; hg19: chr12-21689343;