12-21558177-G-C

Variant names:

• chr12-21558177-G-C
• rs7977474
• NM_021957.4:c.1422+23C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021957.4(GYS2):​c.1422+23C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 1,321,506 control chromosomes in the GnomAD database, including 398,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40451 hom., cov: 31)
  • Exomes 𝑓: 0.78 (357993 hom.)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.56
• Publications: 10 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=-0.96).
• BP6: Variant 12-21558177-G-C is Benign according to our data. Variant chr12-21558177-G-C is described in ClinVar as Benign. ClinVar VariationId is 261466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.1422+23C>G		intron_variant	Intron 11 of 15	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1422+23C>G		intron_variant	Intron 11 of 16		XP_024304728.1
GYS2	XM_006719063.4	c.1191+23C>G		intron_variant	Intron 10 of 14		XP_006719126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1422+23C>G		intron_variant	Intron 11 of 15	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*1424+23C>G		intron_variant	Intron 18 of 22			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.1372C>G		non_coding_transcript_exon_variant	Exon 11 of 11

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110049 AN: 151870 Hom.: 40414 Cov.: 31

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.667

GnomAD2 exomes AF: 0.765 AC: 191420 AN: 250296 AF XY: 0.767

Gnomad AFR exome AF: 0.595

Gnomad AMR exome AF: 0.785

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.750

Gnomad FIN exome AF: 0.807

Gnomad NFE exome AF: 0.778

Gnomad OTH exome AF: 0.731

GnomAD4 exome AF: 0.781 AC: 913207 AN: 1169518 Hom.: 357993 Cov.: 16 AF XY: 0.781 AC XY: 465427 AN XY: 595964

African (AFR) AF: 0.594 AC: 16641 AN: 27994

American (AMR) AF: 0.780 AC: 34549 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 16850 AN: 24316

East Asian (EAS) AF: 0.786 AC: 30090 AN: 38270

South Asian (SAS) AF: 0.792 AC: 63520 AN: 80252

European-Finnish (FIN) AF: 0.804 AC: 42846 AN: 53284

Middle Eastern (MID) AF: 0.633 AC: 3301 AN: 5218

European-Non Finnish (NFE) AF: 0.790 AC: 667483 AN: 845208

Other (OTH) AF: 0.748 AC: 37927 AN: 50690

GnomAD4 genome AF: 0.725 AC: 110142 AN: 151988 Hom.: 40451 Cov.: 31 AF XY: 0.729 AC XY: 54130 AN XY: 74288

African (AFR) AF: 0.602 AC: 24940 AN: 41410

American (AMR) AF: 0.733 AC: 11202 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2388 AN: 3468

East Asian (EAS) AF: 0.751 AC: 3870 AN: 5152

South Asian (SAS) AF: 0.795 AC: 3828 AN: 4814

European-Finnish (FIN) AF: 0.810 AC: 8550 AN: 10558

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53197 AN: 67998

Other (OTH) AF: 0.669 AC: 1410 AN: 2108

Alfa AF: 0.696 Hom.: 3926

Bravo AF: 0.711

Asia WGS AF: 0.751 AC: 2606 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.61
DANN	Benign	0.30
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs7977474; hg19: chr12-21711111;