rs140445396

Variant names:

• chr12-21536695-A-T
• rs140445396
• NM_021957.4:c.*259T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_021957.4(GYS2):​c.*259T>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 0.00473 in 494,024 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (10 hom.)
• Consequence: GYS2 NM_021957.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.197
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00437 (666/152264) while in subpopulation NFE AF = 0.00656 (446/68006). AF 95% confidence interval is 0.00606. There are 1 homozygotes in GnomAd4. There are 321 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
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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.*259T>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.*259T>A		3_prime_UTR	Exon 16 of 16	ENSP00000261195.2	P54840
	ENSG00000285854	ENST00000647960.1		n.*2373T>A		non_coding_transcript_exon	Exon 23 of 23	ENSP00000497202.1	A0A3B3IS95
	ENSG00000285854	ENST00000647960.1		n.*2373T>A		3_prime_UTR	Exon 23 of 23	ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00656

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00490 AC: 1673 AN: 341760 Hom.: 10 Cov.: 0 AF XY: 0.00477 AC XY: 871 AN XY: 182428

African (AFR) AF: 0.000887 AC: 9 AN: 10142

American (AMR) AF: 0.00216 AC: 31 AN: 14370

Ashkenazi Jewish (ASJ) AF: 0.00380 AC: 39 AN: 10266

East Asian (EAS) AF: 0.00 AC: 0 AN: 21250

South Asian (SAS) AF: 0.00144 AC: 58 AN: 40302

European-Finnish (FIN) AF: 0.00968 AC: 173 AN: 17880

Middle Eastern (MID) AF: 0.00204 AC: 3 AN: 1474

European-Non Finnish (NFE) AF: 0.00616 AC: 1272 AN: 206498

Other (OTH) AF: 0.00449 AC: 88 AN: 19578

GnomAD4 genome AF: 0.00437 AC: 666 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00431 AC XY: 321 AN XY: 74454

African (AFR) AF: 0.00108 AC: 45 AN: 41558

American (AMR) AF: 0.00340 AC: 52 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00933 AC: 99 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00656 AC: 446 AN: 68006

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00614 Hom.: 0

Bravo AF: 0.00388

Asia WGS AF: 0.00144 AC: 5 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	-0.90
CADD	Benign	0.99
DANN	Benign	0.50
PhyloP100		0.20
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: rs140445396; hg19: chr12-21689629;