NM_021957.4:c.1229+40T>C

Variant names:

• chr12-21559611-A-G
• rs1871136
• NM_021957.4:c.1229+40T>C

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.1229+40T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 1,045,352 control chromosomes in the GnomAD database, including 304,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42625 hom., cov: 33)
  • Exomes 𝑓: 0.77 (262213 hom.)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.985
• Publications: 9 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=-0.91).
• BP6: Variant 12-21559611-A-G is Benign according to our data. Variant chr12-21559611-A-G is described in ClinVar as Benign. ClinVar VariationId is 261464.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.1229+40T>C		intron_variant	Intron 9 of 15	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1229+40T>C		intron_variant	Intron 9 of 16		XP_024304728.1
GYS2	XM_006719063.4	c.998+40T>C		intron_variant	Intron 8 of 14		XP_006719126.1
GYS2	XM_017019245.3	c.*608T>C		downstream_gene_variant			XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.1229+40T>C		intron_variant	Intron 9 of 15	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*1231+40T>C		intron_variant	Intron 16 of 22			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.1156+40T>C		intron_variant	Intron 9 of 10

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113447 AN: 152066 Hom.: 42588 Cov.: 33

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.684

GnomAD2 exomes AF: 0.768 AC: 188577 AN: 245472 AF XY: 0.769

Gnomad AFR exome AF: 0.668

Gnomad AMR exome AF: 0.786

Gnomad ASJ exome AF: 0.689

Gnomad EAS exome AF: 0.748

Gnomad FIN exome AF: 0.806

Gnomad NFE exome AF: 0.776

Gnomad OTH exome AF: 0.732

GnomAD4 exome AF: 0.765 AC: 683364 AN: 893168 Hom.: 262213 Cov.: 12 AF XY: 0.766 AC XY: 358796 AN XY: 468236

African (AFR) AF: 0.663 AC: 15408 AN: 23224

American (AMR) AF: 0.782 AC: 34140 AN: 43652

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 15580 AN: 22566

East Asian (EAS) AF: 0.785 AC: 29132 AN: 37098

South Asian (SAS) AF: 0.787 AC: 58476 AN: 74278

European-Finnish (FIN) AF: 0.804 AC: 42571 AN: 52966

Middle Eastern (MID) AF: 0.629 AC: 2893 AN: 4600

European-Non Finnish (NFE) AF: 0.766 AC: 454473 AN: 593238

Other (OTH) AF: 0.739 AC: 30691 AN: 41546

GnomAD4 genome AF: 0.746 AC: 113542 AN: 152184 Hom.: 42625 Cov.: 33 AF XY: 0.749 AC XY: 55739 AN XY: 74402

African (AFR) AF: 0.677 AC: 28118 AN: 41522

American (AMR) AF: 0.742 AC: 11348 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2389 AN: 3470

East Asian (EAS) AF: 0.752 AC: 3897 AN: 5184

South Asian (SAS) AF: 0.795 AC: 3834 AN: 4822

European-Finnish (FIN) AF: 0.809 AC: 8576 AN: 10598

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

European-Non Finnish (NFE) AF: 0.782 AC: 53175 AN: 67982

Other (OTH) AF: 0.686 AC: 1448 AN: 2110

Alfa AF: 0.754 Hom.: 14372

Bravo AF: 0.736

Asia WGS AF: 0.755 AC: 2613 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

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	-0.91
CADD	Benign	0.88
DANN	Benign	0.68
PhyloP100		-0.98
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: rs1871136; hg19: chr12-21712545;