rs34097444

chr19-38459219-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):c.2241G>A(p.Leu747=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000893 in 1,614,166 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.79

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 19-38459219-G-A is Benign according to our data. Variant chr19-38459219-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00491 (747/152292) while in subpopulation AFR AF= 0.0157 (654/41568). AF 95% confidence interval is 0.0147. There are 7 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.2241G>A	p.Leu747=	synonymous_variant	19/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.2241G>A	p.Leu747=	synonymous_variant	19/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.2241G>A	p.Leu747=	synonymous_variant	19/105	1		P4
RYR1	ENST00000599547.6	c.2241G>A	p.Leu747=	synonymous_variant, NMD_transcript_variant	19/80	2

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 745 AN: 152174 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00115 AC: 288 AN: 251406 Hom.: 3 AF XY: 0.000964 AC XY: 131 AN XY: 135882

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000475 AC: 695 AN: 1461874 Hom.: 4 Cov.: 33 AF XY: 0.000426 AC XY: 310 AN XY: 727238

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.00491 AC: 747 AN: 152292 Hom.: 7 Cov.: 32 AF XY: 0.00486 AC XY: 362 AN XY: 74470

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00244 Hom.: 3

Bravo AF: 0.00622

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2017	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. -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Malignant hyperthermia, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Malignant hyperthermia of anesthesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Multiminicore myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-Related Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	8.5
Dann	Benign	0.72

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: rs34097444; hg19: chr19-38949859; COSMIC: COSV100617235;