rs6508806

Positions:

• chr19-38528513-A-G
• chr19-38528513-A-T

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.10938-86A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,589,218 control chromosomes in the GnomAD database, including 21,338 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1907 hom., cov: 31)
  • Exomes 𝑓: 0.16 (19431 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.675

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-38528513-A-G is Benign according to our data. Variant chr19-38528513-A-G is described in ClinVar as [Benign]. Clinvar id is 133002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38528513-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10938-86A>G		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10938-86A>G		intron_variant		5	NM_000540.3	A2
	ENST00000597015.1	n.43T>C		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22880 AN: 151860 Hom.: 1896 Cov.: 31

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.158

GnomAD4 exome AF: 0.156 AC: 224574 AN: 1437240 Hom.: 19431 Cov.: 27 AF XY: 0.159 AC XY: 114209 AN XY: 716108

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.287

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.151 AC: 22930 AN: 151978 Hom.: 1907 Cov.: 31 AF XY: 0.154 AC XY: 11436 AN XY: 74284

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.163

Alfa AF: 0.0557 Hom.: 61

Bravo AF: 0.153

Asia WGS AF: 0.324 AC: 1124 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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
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	-0.90
CADD	Benign	0.52
DANN	Benign	0.28

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: rs6508806; hg19: chr19-39019153; COSMIC: COSV62103830; COSMIC: COSV62103830;