12-21546491-T-C

Variant names:

• chr12-21546491-T-C
• rs73238708
• NM_021957.4:c.1423-21A>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.1423-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,551,594 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (37 hom.)
• Consequence: GYS2 NM_021957.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.572
• 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=-0.79).
• BP6: Variant 12-21546491-T-C is Benign according to our data. Variant chr12-21546491-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1877/151414) while in subpopulation AFR AF = 0.037 (1525/41234). AF 95% confidence interval is 0.0354. There are 35 homozygotes in GnomAd4. There are 880 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.1423-21A>G		intron_variant	Intron 11 of 15	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.1423-21A>G		intron_variant	Intron 11 of 16		XP_024304728.1
GYS2	XM_006719063.4	c.1192-21A>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.1423-21A>G		intron_variant	Intron 11 of 15	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*1425-21A>G		intron_variant	Intron 18 of 22			ENSP00000497202.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1873 AN: 151300 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00921

Gnomad ASJ AF: 0.00752

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.000289

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00499 AC: 1030 AN: 206216 AF XY: 0.00418

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.00676

Gnomad ASJ exome AF: 0.00639

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000319

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00527

GnomAD4 exome AF: 0.00288 AC: 4026 AN: 1400180 Hom.: 37 Cov.: 24 AF XY: 0.00285 AC XY: 1982 AN XY: 696554

African (AFR) AF: 0.0391 AC: 1231 AN: 31522

American (AMR) AF: 0.00704 AC: 291 AN: 41344

Ashkenazi Jewish (ASJ) AF: 0.00678 AC: 171 AN: 25206

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38320

South Asian (SAS) AF: 0.000606 AC: 49 AN: 80908

European-Finnish (FIN) AF: 0.000255 AC: 13 AN: 51028

Middle Eastern (MID) AF: 0.0144 AC: 79 AN: 5484

European-Non Finnish (NFE) AF: 0.00173 AC: 1844 AN: 1068360

Other (OTH) AF: 0.00598 AC: 347 AN: 58008

GnomAD4 genome AF: 0.0124 AC: 1877 AN: 151414 Hom.: 35 Cov.: 32 AF XY: 0.0119 AC XY: 880 AN XY: 73962

African (AFR) AF: 0.0370 AC: 1525 AN: 41234

American (AMR) AF: 0.00920 AC: 140 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00752 AC: 26 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.000289 AC: 3 AN: 10390

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 67862

Other (OTH) AF: 0.0185 AC: 39 AN: 2106

Alfa AF: 0.00759 Hom.: 9

Bravo AF: 0.0139

Asia WGS AF: 0.00520 AC: 19 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 26, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.79
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		0.57
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: rs73238708; hg19: chr12-21699425;