rs2287754

Variant names:

• chr19-48993237-G-A
• rs2287754
• NM_002103.5:c.-125C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-48993237-G-A
• chr19-48993237-G-C
• chr19-48993237-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002103.5(GYS1):​c.-125C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 758,922 control chromosomes in the GnomAD database, including 2,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (506 hom., cov: 32)
  • Exomes 𝑓: 0.079 (2251 hom.)
• Consequence: GYS1 NM_002103.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.283
• Publications: 19 publications found

Genes affected

GYS1 (HGNC:4706): (glycogen synthase 1) The protein encoded by this gene catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of alpha-1,4-glycoside linkages. Mutations in this gene are associated with muscle glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

RUVBL2 (HGNC:10475): (RuvB like AAA ATPase 2) This gene encodes the second human homologue of the bacterial RuvB gene. Bacterial RuvB protein is a DNA helicase essential for homologous recombination and DNA double-strand break repair. Functional analysis showed that this gene product has both ATPase and DNA helicase activities. This gene is physically linked to the CGB/LHB gene cluster on chromosome 19q13.3, and is very close (55 nt) to the LHB gene, in the opposite orientation. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-48993237-G-A is Benign according to our data. Variant chr19-48993237-G-A is described in ClinVar as Benign. ClinVar VariationId is 329833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS1	NM_002103.5	c.-125C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	ENST00000323798.8	NP_002094.2
GYS1	NM_002103.5	c.-125C>T		5_prime_UTR_variant	Exon 1 of 16	ENST00000323798.8	NP_002094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS1	ENST00000323798.8	c.-125C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	1	NM_002103.5	ENSP00000317904.3
GYS1	ENST00000323798.8	c.-125C>T		5_prime_UTR_variant	Exon 1 of 16	1	NM_002103.5	ENSP00000317904.3

Frequencies

GnomAD3 genomes AF: 0.0745 AC: 11325 AN: 152094 Hom.: 505 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.0761

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0785

Gnomad OTH AF: 0.0804

GnomAD2 exomes AF: 0.0840 AC: 19041 AN: 226674 AF XY: 0.0778

Gnomad AFR exome AF: 0.0415

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.0536

Gnomad EAS exome AF: 0.0864

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.0792

Gnomad OTH exome AF: 0.0822

GnomAD4 exome AF: 0.0789 AC: 47860 AN: 606708 Hom.: 2251 Cov.: 5 AF XY: 0.0751 AC XY: 24933 AN XY: 331978

African (AFR) AF: 0.0441 AC: 771 AN: 17464

American (AMR) AF: 0.147 AC: 6345 AN: 43070

Ashkenazi Jewish (ASJ) AF: 0.0558 AC: 1158 AN: 20738

East Asian (EAS) AF: 0.0755 AC: 2684 AN: 35552

South Asian (SAS) AF: 0.0277 AC: 1904 AN: 68856

European-Finnish (FIN) AF: 0.136 AC: 5211 AN: 38334

Middle Eastern (MID) AF: 0.0585 AC: 175 AN: 2992

European-Non Finnish (NFE) AF: 0.0780 AC: 27101 AN: 347322

Other (OTH) AF: 0.0775 AC: 2511 AN: 32380

GnomAD4 genome AF: 0.0745 AC: 11335 AN: 152214 Hom.: 506 Cov.: 32 AF XY: 0.0765 AC XY: 5695 AN XY: 74430

African (AFR) AF: 0.0413 AC: 1717 AN: 41546

American (AMR) AF: 0.118 AC: 1801 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3472

East Asian (EAS) AF: 0.0767 AC: 396 AN: 5166

South Asian (SAS) AF: 0.0273 AC: 132 AN: 4832

European-Finnish (FIN) AF: 0.136 AC: 1441 AN: 10604

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0785 AC: 5335 AN: 67992

Other (OTH) AF: 0.0819 AC: 173 AN: 2112

Alfa AF: 0.0718 Hom.: 547

Bravo AF: 0.0731

Asia WGS AF: 0.0650 AC: 228 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glycogen storage disease due to muscle and heart glycogen synthase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.1
DANN	Benign	0.88
PhyloP100		-0.28
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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: rs2287754; hg19: chr19-49496494; COSMIC: COSV107207528; COSMIC: COSV107207528;