12-21536695-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_021957.4(GYS2):​c.*259T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 494,024 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0044 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0049 ( 10 hom. )

Consequence

GYS2
NM_021957.4 3_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.197
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00437 (666/152264) while in subpopulation NFE AF= 0.00656 (446/68006). AF 95% confidence interval is 0.00606. There are 1 homozygotes in gnomad4. There are 321 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GYS2NM_021957.4 linkuse as main transcriptc.*259T>A 3_prime_UTR_variant 16/16 ENST00000261195.3
LOC124902896XR_007063240.1 linkuse as main transcriptn.519-351A>T intron_variant, non_coding_transcript_variant
GYS2XM_006719063.4 linkuse as main transcriptc.*259T>A 3_prime_UTR_variant 15/15
GYS2XM_024448960.2 linkuse as main transcriptc.*42+217T>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GYS2ENST00000261195.3 linkuse as main transcriptc.*259T>A 3_prime_UTR_variant 16/161 NM_021957.4 P1
SPXENST00000537527.1 linkuse as main transcriptn.472-351A>T intron_variant, non_coding_transcript_variant 3
SPXENST00000649016.1 linkuse as main transcriptn.529-351A>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00437
AC:
665
AN:
152146
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00109
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00341
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00933
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.00656
Gnomad OTH
AF:
0.00382
GnomAD4 exome
AF:
0.00490
AC:
1673
AN:
341760
Hom.:
10
Cov.:
0
AF XY:
0.00477
AC XY:
871
AN XY:
182428
show subpopulations
Gnomad4 AFR exome
AF:
0.000887
Gnomad4 AMR exome
AF:
0.00216
Gnomad4 ASJ exome
AF:
0.00380
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00144
Gnomad4 FIN exome
AF:
0.00968
Gnomad4 NFE exome
AF:
0.00616
Gnomad4 OTH exome
AF:
0.00449
GnomAD4 genome
AF:
0.00437
AC:
666
AN:
152264
Hom.:
1
Cov.:
32
AF XY:
0.00431
AC XY:
321
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.00108
Gnomad4 AMR
AF:
0.00340
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.00933
Gnomad4 NFE
AF:
0.00656
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.00614
Hom.:
0
Bravo
AF:
0.00388
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.99
DANN
Benign
0.50

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.

Other links and lift over

dbSNP: rs140445396; hg19: chr12-21689629; API