19-48993237-G-A

Variant names:

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002103.5. 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
	GYS1	NM_002103.5	MANE Select	c.-125C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_002094.2
	GYS1	NM_002103.5	MANE Select	c.-125C>T		5_prime_UTR	Exon 1 of 16	NP_002094.2
	GYS1	NM_001161587.2		c.-125C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001155059.1	P13807-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS1	ENST00000323798.8	TSL:1 MANE Select	c.-125C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000317904.3	P13807-1
	GYS1	ENST00000263276.6	TSL:1	c.-125C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000263276.6	P13807-2
	GYS1	ENST00000323798.8	TSL:1 MANE Select	c.-125C>T		5_prime_UTR	Exon 1 of 16	ENSP00000317904.3	P13807-1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glycogen storage disease due to muscle and heart glycogen synthase deficiency (1)

Computational scores

Source: dbNSFP v4.9

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;