chr12-21536664-C-A

Variant names:

• chr12-21536664-C-A
• rs17849015
• NM_021957.4:c.*290G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BS1 BS2_Supporting

The NM_021957.4(GYS2):​c.*290G>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 0.000676 in 427,396 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (2 hom.)
• Consequence: GYS2 NM_021957.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0140
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-21536664-C-A is Benign according to our data. Variant chr12-21536664-C-A is described in ClinVar as Benign. ClinVar VariationId is 884061.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000447 (68/152146) while in subpopulation EAS AF = 0.0112 (58/5174). AF 95% confidence interval is 0.0089. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited 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.*290G>T		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.*290G>T		3_prime_UTR	Exon 16 of 16	ENSP00000261195.2	P54840
	ENSG00000285854	ENST00000647960.1		n.*2404G>T		non_coding_transcript_exon	Exon 23 of 23	ENSP00000497202.1	A0A3B3IS95
	ENSG00000285854	ENST00000647960.1		n.*2404G>T		3_prime_UTR	Exon 23 of 23	ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000803 AC: 221 AN: 275250 Hom.: 2 Cov.: 0 AF XY: 0.000898 AC XY: 133 AN XY: 148050

African (AFR) AF: 0.00 AC: 0 AN: 8340

American (AMR) AF: 0.0000836 AC: 1 AN: 11966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7912

East Asian (EAS) AF: 0.0103 AC: 153 AN: 14844

South Asian (SAS) AF: 0.00122 AC: 47 AN: 38634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12702

Middle Eastern (MID) AF: 0.000859 AC: 1 AN: 1164

European-Non Finnish (NFE) AF: 0.0000182 AC: 3 AN: 164524

Other (OTH) AF: 0.00106 AC: 16 AN: 15164

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.000635

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

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	-0.82
CADD	Benign	1.2
DANN	Benign	0.42
PhyloP100		0.014

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: rs17849015; hg19: chr12-21689598;