chr19-38502998-A-G

Position:

• chr19-38502998-A-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.7926+28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,598,578 control chromosomes in the GnomAD database, including 72,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10022 hom., cov: 31)
  • Exomes 𝑓: 0.29 (62898 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.51

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=-0.85).
• BP6: Variant 19-38502998-A-G is Benign according to our data. Variant chr19-38502998-A-G is described in ClinVar as [Benign]. Clinvar id is 133216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38502998-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7926+28A>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.7926+28A>G		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.7926+28A>G		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.1378+28A>G		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.7926+28A>G		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52935 AN: 151798 Hom.: 9983 Cov.: 31

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.349

GnomAD3 exomes AF: 0.337 AC: 81492 AN: 241472 Hom.: 14720 AF XY: 0.335 AC XY: 43861 AN XY: 131100

Gnomad AFR exome AF: 0.486

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.346

Gnomad SAS exome AF: 0.450

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.264

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.287 AC: 414744 AN: 1446662 Hom.: 62898 Cov.: 34 AF XY: 0.291 AC XY: 209244 AN XY: 720132

Gnomad4 AFR exome AF: 0.480

Gnomad4 AMR exome AF: 0.437

Gnomad4 ASJ exome AF: 0.266

Gnomad4 EAS exome AF: 0.341

Gnomad4 SAS exome AF: 0.440

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.305

GnomAD4 genome AF: 0.349 AC: 53037 AN: 151916 Hom.: 10022 Cov.: 31 AF XY: 0.356 AC XY: 26451 AN XY: 74264

Gnomad4 AFR AF: 0.477

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.450

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.353

Alfa AF: 0.282 Hom.: 1838

Bravo AF: 0.358

Asia WGS AF: 0.492 AC: 1709 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

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 provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
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 25, 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	-0.85
CADD	Benign	0.25
DANN	Benign	0.38

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: rs1469699; hg19: chr19-38993638; COSMIC: COSV62091654;