12-21539276-T-G

Variant names:

• chr12-21539276-T-G
• rs142883971
• NM_021957.4:c.1872A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021957.4(GYS2):​c.1872A>C​(p.Glu624Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E624E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GYS2 NM_021957.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130
• 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]

ENSG00000285854 (HGNC:):

SPX (HGNC:28139): (spexin hormone) The protein encoded by this gene is a hormone involved in modulation of cardiovascular and renal function. It has also been shown in rats to cause weight loss. Several transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14306542).

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.1872A>C	p.Glu624Asp	missense	Exon 15 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.1872A>C	p.Glu624Asp	missense	Exon 15 of 16	ENSP00000261195.2	P54840
	ENSG00000285854	ENST00000647960.1		n.*1874A>C		non_coding_transcript_exon	Exon 22 of 23	ENSP00000497202.1	A0A3B3IS95
	ENSG00000285854	ENST00000647960.1		n.*1874A>C		3_prime_UTR	Exon 22 of 23	ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435516 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 715990

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32936

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088104

Other (OTH) AF: 0.00 AC: 0 AN: 59528

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.2
DANN	Benign	0.93
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.13
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.070
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.48		Gain of catalytic residue at P628 (P = 0.001)
MVP		0.56
MPC		0.11
ClinPred		0.99	D
GERP RS		-3.7
Varity_R		0.045
gMVP		0.17
Mutation Taster		=83/17	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: rs142883971; hg19: chr12-21692210;