12-21537006-A-T

Position:

chr12-21537006-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021957.4(GYS2):c.2060T>A(p.Leu687Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

GYS2
NM_021957.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.53

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 links:

ENSG00000285854 (HGNC:):

ENSG00000285854 links:

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]

SPX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11628407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYS2	NM_021957.4 link	c.2060T>A	p.Leu687Gln	missense_variant	16/16	ENST00000261195.3	NP_068776.2	P54840
GYS2	XM_024448960.2 link	c.2060T>A	p.Leu687Gln	missense_variant	16/17		XP_024304728.1
GYS2	XM_006719063.4 link	c.1829T>A	p.Leu610Gln	missense_variant	15/15		XP_006719126.1
LOC124902896	XR_007063240.1 link	n.519-40A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GYS2	ENST00000261195.3 link	c.2060T>A	p.Leu687Gln	missense_variant	16/16	1	NM_021957.4	ENSP00000261195.2	P54840
ENSG00000285854	ENST00000647960.1 link	n.*2062T>A		non_coding_transcript_exon_variant	23/23			ENSP00000497202.1	A0A3B3IS95
ENSG00000285854	ENST00000647960.1 link	n.*2062T>A		3_prime_UTR_variant	23/23			ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251166

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000201

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:

0.00000989

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.2060T>A (p.L687Q) alteration is located in exon 16 (coding exon 16) of the GYS2 gene. This alteration results from a T to A substitution at nucleotide position 2060, causing the leucine (L) at amino acid position 687 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

M_CAP

Benign

0.058

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.81

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.63

REVEL

Benign

0.27

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.043

Polyphen

0.38

Vest4

0.47

MVP

0.73

MPC

0.30

ClinPred

0.24

GERP RS

3.1

Varity_R

0.20

gMVP

0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over