NM_021957.4:c.1464A>G

Variant names:

• chr12-21546429-T-C
• rs35403985
• NM_021957.4:c.1464A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021957.4(GYS2):​c.1464A>G​(p.Leu488Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,588,494 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (143 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (144 hom.)
• Consequence: GYS2 NM_021957.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.364
• Publications: 2 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp

ENSG00000285854 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-21546429-T-C is Benign according to our data. Variant chr12-21546429-T-C is described in ClinVar as Benign. ClinVar VariationId is 137525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.364 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0781 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021957.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	NM_021957.4	MANE Select	c.1464A>G	p.Leu488Leu	synonymous	Exon 12 of 16	NP_068776.2	P54840

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	ENST00000261195.3	TSL:1 MANE Select	c.1464A>G	p.Leu488Leu	synonymous	Exon 12 of 16	ENSP00000261195.2	P54840
	ENSG00000285854	ENST00000647960.1		n.*1466A>G		non_coding_transcript_exon	Exon 19 of 23	ENSP00000497202.1	A0A3B3IS95
	ENSG00000285854	ENST00000647960.1		n.*1466A>G		3_prime_UTR	Exon 19 of 23	ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3569 AN: 151700 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00833

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00675 AC: 1684 AN: 249620 AF XY: 0.00510

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00279 AC: 4013 AN: 1436678 Hom.: 144 Cov.: 26 AF XY: 0.00249 AC XY: 1780 AN XY: 716128

African (AFR) AF: 0.0864 AC: 2849 AN: 32978

American (AMR) AF: 0.00368 AC: 164 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 401 AN: 25902

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39522

South Asian (SAS) AF: 0.000199 AC: 17 AN: 85490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00631 AC: 36 AN: 5702

European-Non Finnish (NFE) AF: 0.000165 AC: 180 AN: 1089736

Other (OTH) AF: 0.00613 AC: 365 AN: 59532

GnomAD4 genome AF: 0.0235 AC: 3572 AN: 151816 Hom.: 143 Cov.: 32 AF XY: 0.0227 AC XY: 1687 AN XY: 74204

African (AFR) AF: 0.0804 AC: 3325 AN: 41356

American (AMR) AF: 0.00832 AC: 127 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67942

Other (OTH) AF: 0.0142 AC: 30 AN: 2108

Alfa AF: 0.0145 Hom.: 43

Bravo AF: 0.0266

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000475

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disorder due to hepatic glycogen synthase deficiency (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.0
DANN	Benign	0.62
PhyloP100		-0.36
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: rs35403985; hg19: chr12-21699363;