rs139882761

Variant names:

• chr12-21559148-G-A
• rs139882761
• NM_021957.4:c.1251C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-21559148-G-A
• chr12-21559148-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_021957.4(GYS2):​c.1251C>T​(p.Asn417Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,606,610 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: GYS2 NM_021957.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.07
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 12-21559148-G-A is Benign according to our data. Variant chr12-21559148-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261465.
• BP7: Synonymous conserved (PhyloP=3.07 with no splicing effect.

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.1251C>T	p.Asn417Asn	synonymous	Exon 10 of 16	NP_068776.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	ENST00000261195.3	TSL:1 MANE Select	c.1251C>T	p.Asn417Asn	synonymous	Exon 10 of 16	ENSP00000261195.2
	ENSG00000285854	ENST00000647960.1		n.*1253C>T		non_coding_transcript_exon	Exon 17 of 23	ENSP00000497202.1
	ENSG00000285854	ENST00000647960.1		n.*1253C>T		3_prime_UTR	Exon 17 of 23	ENSP00000497202.1

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151828 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000475 AC: 119 AN: 250704 AF XY: 0.000398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00855

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000224 AC: 326 AN: 1454782 Hom.: 0 Cov.: 27 AF XY: 0.000238 AC XY: 172 AN XY: 724060

African (AFR) AF: 0.0000300 AC: 1 AN: 33346

American (AMR) AF: 0.000112 AC: 5 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00830 AC: 216 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.0000815 AC: 7 AN: 85882

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.0000569 AC: 63 AN: 1106386

Other (OTH) AF: 0.000549 AC: 33 AN: 60088

GnomAD4 genome AF: 0.000303 AC: 46 AN: 151828 Hom.: 1 Cov.: 32 AF XY: 0.000297 AC XY: 22 AN XY: 74138

African (AFR) AF: 0.0000484 AC: 2 AN: 41324

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.000246

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Glycogen storage disorder due to hepatic glycogen synthase deficiency (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.6
DANN	Benign	0.59
PhyloP100		3.1
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: rs139882761; hg19: chr12-21712082; COSMIC: COSV53925061;