rs150691568

Variant names:

• chr12-21560507-G-C
• rs150691568
• NM_021957.4:c.1063-15C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021957.4(GYS2):​c.1063-15C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000654 in 1,141,222 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (12 hom.)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.56
• 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]

GYS2 Gene-Disease associations (from GenCC):

• glycogen storage disorder due to hepatic glycogen synthase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ENSG00000285854 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-21560507-G-C is Benign according to our data. Variant chr12-21560507-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000355 (54/152240) while in subpopulation EAS AF = 0.0102 (53/5184). AF 95% confidence interval is 0.00803. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.1063-15C>G		intron_variant	Intron 7 of 15	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1063-15C>G		intron_variant	Intron 7 of 16		XP_024304728.1
GYS2	XM_006719063.4	c.832-15C>G		intron_variant	Intron 6 of 14		XP_006719126.1
GYS2	XM_017019245.3	c.1063-15C>G		intron_variant	Intron 7 of 8		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1063-15C>G		intron_variant	Intron 7 of 15	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*1065-15C>G		intron_variant	Intron 14 of 22			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.990-15C>G		intron_variant	Intron 7 of 10

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000402 AC: 101 AN: 251184 AF XY: 0.000413

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00506

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000700 AC: 692 AN: 988982 Hom.: 12 Cov.: 14 AF XY: 0.000677 AC XY: 347 AN XY: 512436

African (AFR) AF: 0.0000402 AC: 1 AN: 24884

American (AMR) AF: 0.0000453 AC: 2 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23346

East Asian (EAS) AF: 0.0164 AC: 617 AN: 37554

South Asian (SAS) AF: 0.0000390 AC: 3 AN: 76832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4966

European-Non Finnish (NFE) AF: 0.00000147 AC: 1 AN: 679248

Other (OTH) AF: 0.00151 AC: 68 AN: 44888

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74442

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0102 AC: 53 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

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

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000332

Asia WGS AF: 0.00462 AC: 16 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Glycogen storage disorder due to hepatic glycogen synthase deficiency Benign:2

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.74
PhyloP100		2.6
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: rs150691568; hg19: chr12-21713441; COSMIC: COSV53923780;