chr12-21536695-A-T

Position:

• chr12-21536695-A-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYS2	NM_021957.4	c.*259T>A		3_prime_UTR_variant	16/16	ENST00000261195.3
LOC124902896	XR_007063240.1	n.519-351A>T		intron_variant, non_coding_transcript_variant
GYS2	XM_006719063.4	c.*259T>A		3_prime_UTR_variant	15/15
GYS2	XM_024448960.2	c.*42+217T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS2	ENST00000261195.3	c.*259T>A		3_prime_UTR_variant	16/16	1	NM_021957.4	P1
SPX	ENST00000537527.1	n.472-351A>T		intron_variant, non_coding_transcript_variant		3
SPX	ENST00000649016.1	n.529-351A>T		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.000887

Gnomad4 AMR exome AF: 0.00216

Gnomad4 ASJ exome AF: 0.00380

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.00968

Gnomad4 NFE exome AF: 0.00616

Gnomad4 OTH exome AF: 0.00449

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

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00933

Gnomad4 NFE AF: 0.00656

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00614 Hom.: 0

Bravo AF: 0.00388

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.99
DANN	Benign	0.50

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: rs140445396; hg19: chr12-21689629;