12-21563024-T-G

Variant names:

• chr12-21563024-T-G
• NM_021957.4:c.956A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021957.4(GYS2):​c.956A>C​(p.Asp319Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,928 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GYS2 NM_021957.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.95

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]

ENSG00000285854 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS2	NM_021957.4	c.956A>C	p.Asp319Ala	missense_variant	Exon 7 of 16	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2	c.956A>C	p.Asp319Ala	missense_variant	Exon 7 of 17		XP_024304728.1
GYS2	XM_006719063.4	c.725A>C	p.Asp242Ala	missense_variant	Exon 6 of 15		XP_006719126.1
GYS2	XM_017019245.3	c.956A>C	p.Asp319Ala	missense_variant	Exon 7 of 9		XP_016874734.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS2	ENST00000261195.3	c.956A>C	p.Asp319Ala	missense_variant	Exon 7 of 16	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1	n.*958A>C		non_coding_transcript_exon_variant	Exon 14 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000647960.1	n.*958A>C		3_prime_UTR_variant	Exon 14 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1	n.883A>C		non_coding_transcript_exon_variant	Exon 7 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459928 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.087	B
Vest4		0.54
MutPred		0.65		Gain of catalytic residue at D317 (P = 5e-04);
MVP		0.80
MPC		0.19
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.53
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-21715958;