19-38505980-C-T

Position:

• chr19-38505980-C-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.8541+34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,552,680 control chromosomes in the GnomAD database, including 65,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8405 hom., cov: 29)
  • Exomes 𝑓: 0.27 (56850 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.219

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=-0.94).
• BP6: Variant 19-38505980-C-T is Benign according to our data. Variant chr19-38505980-C-T is described in ClinVar as [Benign]. Clinvar id is 133227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38505980-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8541+34C>T		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8541+34C>T		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.8541+34C>T		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.1993+34C>T		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.8541+34C>T		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.325 AC: 48722 AN: 149882 Hom.: 8368 Cov.: 29

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.314

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.319 AC: 76408 AN: 239744 Hom.: 12811 AF XY: 0.319 AC XY: 41699 AN XY: 130758

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.336

Gnomad SAS exome AF: 0.456

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.265 AC: 372072 AN: 1402678 Hom.: 56850 Cov.: 33 AF XY: 0.271 AC XY: 189274 AN XY: 699538

Gnomad4 AFR exome AF: 0.427

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.248

Gnomad4 EAS exome AF: 0.336

Gnomad4 SAS exome AF: 0.444

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.237

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.325 AC: 48821 AN: 150002 Hom.: 8405 Cov.: 29 AF XY: 0.333 AC XY: 24347 AN XY: 73166

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.358

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.338

Alfa AF: 0.271 Hom.: 1060

Bravo AF: 0.332

Asia WGS AF: 0.483 AC: 1677 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2013

- -

Congenital multicore myopathy with external ophthalmoplegia 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

- -

Central core myopathy 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	-0.94
CADD	Benign	0.62
DANN	Benign	0.76

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: rs2960342; hg19: chr19-38996620; COSMIC: COSV62092761;