19-48970770-A-T

Variant names:

• chr19-48970770-A-T
• rs2270938
• NM_002103.5:c.1646-61T>A

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.1646-61T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 1,534,400 control chromosomes in the GnomAD database, including 112,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11944 hom., cov: 30)
  • Exomes 𝑓: 0.38 (100753 hom.)
• Consequence: GYS1 NM_002103.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0610
• Publications: 10 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]

GYS1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to muscle and heart glycogen synthase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-48970770-A-T is Benign according to our data. Variant chr19-48970770-A-T is described in CliVar as Benign. Clinvar id is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48970770-A-T is described in CliVar as Benign. Clinvar id is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48970770-A-T is described in CliVar as Benign. Clinvar id is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48970770-A-T is described in CliVar as Benign. Clinvar id is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48970770-A-T is described in CliVar as Benign. Clinvar id is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48970770-A-T is described in CliVar as Benign. Clinvar id is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48970770-A-T is described in CliVar as Benign. Clinvar id is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48970770-A-T is described in CliVar as Benign. Clinvar id is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48970770-A-T is described in CliVar as Benign. Clinvar id is 676132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS1	NM_002103.5	c.1646-61T>A		intron_variant	Intron 13 of 15	ENST00000323798.8	NP_002094.2
GYS1	NM_001161587.2	c.1454-61T>A		intron_variant	Intron 12 of 14		NP_001155059.1
GYS1	NR_027763.2	n.1661-61T>A		intron_variant	Intron 12 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS1	ENST00000323798.8	c.1646-61T>A		intron_variant	Intron 13 of 15	1	NM_002103.5	ENSP00000317904.3

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59799 AN: 151462 Hom.: 11926 Cov.: 30

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.397

GnomAD4 exome AF: 0.380 AC: 525635 AN: 1382820 Hom.: 100753 Cov.: 22 AF XY: 0.380 AC XY: 262614 AN XY: 691684

African (AFR) AF: 0.455 AC: 14522 AN: 31950

American (AMR) AF: 0.330 AC: 14506 AN: 43956

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 11870 AN: 25630

East Asian (EAS) AF: 0.384 AC: 15024 AN: 39166

South Asian (SAS) AF: 0.324 AC: 27233 AN: 84022

European-Finnish (FIN) AF: 0.348 AC: 18373 AN: 52748

Middle Eastern (MID) AF: 0.463 AC: 2362 AN: 5104

European-Non Finnish (NFE) AF: 0.383 AC: 399659 AN: 1042678

Other (OTH) AF: 0.384 AC: 22086 AN: 57566

GnomAD4 genome AF: 0.395 AC: 59862 AN: 151580 Hom.: 11944 Cov.: 30 AF XY: 0.390 AC XY: 28904 AN XY: 74056

African (AFR) AF: 0.451 AC: 18592 AN: 41262

American (AMR) AF: 0.338 AC: 5144 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1588 AN: 3472

East Asian (EAS) AF: 0.373 AC: 1915 AN: 5128

South Asian (SAS) AF: 0.311 AC: 1493 AN: 4798

European-Finnish (FIN) AF: 0.351 AC: 3688 AN: 10514

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.385 AC: 26116 AN: 67864

Other (OTH) AF: 0.402 AC: 846 AN: 2106

Alfa AF: 0.386 Hom.: 1359

Bravo AF: 0.397

Asia WGS AF: 0.301 AC: 1049 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.8
DANN	Benign	0.93
PhyloP100		-0.061
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs2270938; hg19: chr19-49474027; COSMIC: COSV54402994; COSMIC: COSV54402994;