rs2960337

Positions:

• chr19-38511974-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.9173-98T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,384,122 control chromosomes in the GnomAD database, including 25,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3718 hom., cov: 31)
  • Exomes 𝑓: 0.17 (21581 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.660

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-38511974-T-G is Benign according to our data. Variant chr19-38511974-T-G is described in ClinVar as [Benign]. Clinvar id is 133239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38511974-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.9173-98T>G		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.9173-98T>G		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.9173-98T>G		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.2575-98T>G		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.9173-271T>G		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31752 AN: 151796 Hom.: 3698 Cov.: 31

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.175 AC: 215140 AN: 1232208 Hom.: 21581 AF XY: 0.180 AC XY: 111316 AN XY: 617016

Gnomad4 AFR exome AF: 0.270

Gnomad4 AMR exome AF: 0.299

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.209 AC: 31821 AN: 151914 Hom.: 3718 Cov.: 31 AF XY: 0.214 AC XY: 15866 AN XY: 74250

Gnomad4 AFR AF: 0.283

Gnomad4 AMR AF: 0.244

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.217

Alfa AF: 0.174 Hom.: 5075

Bravo AF: 0.216

Asia WGS AF: 0.362 AC: 1257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.5
DANN	Benign	0.66

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

Other links and lift over

dbSNP: rs2960337; hg19: chr19-39002614;