Genetic Variant GYS2:p.Asp415Glu (chr12-21559154-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_021957.4(GYS2):c.1245C>A(p.Asp415Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D415D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GYS2
NM_021957.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.525

Publications

0 publications found

Variant links:

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)

GYS2 links:

ENSG00000285854 (HGNC:):

ENSG00000285854 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GYS2	NM_021957.4 link	c.1245C>A	p.Asp415Glu	missense_variant	Exon 10 of 16	ENST00000261195.3	NP_068776.2
GYS2	XM_024448960.2 link	c.1245C>A	p.Asp415Glu	missense_variant	Exon 10 of 17		XP_024304728.1
GYS2	XM_006719063.4 link	c.1014C>A	p.Asp338Glu	missense_variant	Exon 9 of 15		XP_006719126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GYS2	ENST00000261195.3 link	c.1245C>A	p.Asp415Glu	missense_variant	Exon 10 of 16	1	NM_021957.4	ENSP00000261195.2
ENSG00000285854	ENST00000647960.1 link	n.*1247C>A		non_coding_transcript_exon_variant	Exon 17 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000647960.1 link	n.*1247C>A		3_prime_UTR_variant	Exon 17 of 23			ENSP00000497202.1
ENSG00000285854	ENST00000648372.1 link	n.1172C>A		non_coding_transcript_exon_variant	Exon 10 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453574

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723530

African (AFR)

AF:

0.00

AC:

AN:

33248

American (AMR)

AF:

0.00

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39444

South Asian (SAS)

AF:

0.00

AC:

AN:

85850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105290

Other (OTH)

AF:

0.00

AC:

AN:

60060

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-0.68

MutationAssessor

Benign

2.0

PhyloP100

0.53

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.2

REVEL

Benign

0.13

Sift

Benign

0.21

Sift4G

Benign

0.24

Polyphen

0.99

Vest4

0.21

MutPred

0.19

Gain of catalytic residue at L416 (P = 0.0186);

MVP

0.76

MPC

0.39

ClinPred

0.93

GERP RS

1.7

Varity_R

0.11

gMVP

0.62

Mutation Taster

=86/14

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over