rs2960346

Positions:

• chr19-38506995-A-C

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.8816+43A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,610,100 control chromosomes in the GnomAD database, including 67,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8612 hom., cov: 31)
  • Exomes 𝑓: 0.28 (58607 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.149

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=-0.9).
• BP6: Variant 19-38506995-A-C is Benign according to our data. Variant chr19-38506995-A-C is described in ClinVar as [Benign]. Clinvar id is 133235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38506995-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8816+43A>C		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8816+43A>C		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.8816+43A>C		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.2268+43A>C		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.8816+43A>C		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49391 AN: 151700 Hom.: 8576 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.320 AC: 79479 AN: 248248 Hom.: 13590 AF XY: 0.320 AC XY: 43047 AN XY: 134562

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.338

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.275 AC: 401713 AN: 1458282 Hom.: 58607 Cov.: 36 AF XY: 0.280 AC XY: 203096 AN XY: 725418

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.338

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.292

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.326 AC: 49488 AN: 151818 Hom.: 8612 Cov.: 31 AF XY: 0.333 AC XY: 24712 AN XY: 74172

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.289

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.338

Alfa AF: 0.276 Hom.: 1137

Bravo AF: 0.333

Asia WGS AF: 0.487 AC: 1690 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 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	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2013

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Central core myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

King Denborough syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.1
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: rs2960346; hg19: chr19-38997635; COSMIC: COSV62097219; COSMIC: COSV62097219;