12-21536516-T-TA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_021957.4(GYS2):c.*437_*438insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 190,982 control chromosomes in the GnomAD database, including 187 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (187 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (0 hom.)
• Consequence: GYS2 NM_021957.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.412

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 -10 ACMG points.

• BP6: Variant 12-21536516-T-TA is Benign according to our data. Variant chr12-21536516-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 307981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYS2	NM_021957.4	c.*437_*438insT		3_prime_UTR_variant	16/16	ENST00000261195.3
LOC124902896	XR_007063240.1	n.519-524dup		intron_variant, non_coding_transcript_variant
GYS2	XM_006719063.4	c.*437_*438insT		3_prime_UTR_variant	15/15
GYS2	XM_024448960.2	c.*42+395_*42+396insT		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS2	ENST00000261195.3	c.*437_*438insT		3_prime_UTR_variant	16/16	1	NM_021957.4	P1
SPX	ENST00000537527.1	n.472-524dup		intron_variant, non_coding_transcript_variant		3
SPX	ENST00000649016.1	n.529-524dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4315 AN: 152034 Hom.: 186 Cov.: 32

Gnomad AFR AF: 0.0911

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000945

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0311

GnomAD4 exome AF: 0.00412 AC: 160 AN: 38830 Hom.: 0 Cov.: 0 AF XY: 0.00384 AC XY: 76 AN XY: 19812

Gnomad4 AFR exome AF: 0.0625

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.00409

Gnomad4 EAS exome AF: 0.0110

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.00643

GnomAD4 genome AF: 0.0284 AC: 4326 AN: 152152 Hom.: 187 Cov.: 32 AF XY: 0.0276 AC XY: 2054 AN XY: 74386

Gnomad4 AFR AF: 0.0911

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000945

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.0308

Bravo AF: 0.0317

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs60154469; hg19: chr12-21689450;