rs75181912

Positions:

• chr19-38494461-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000540.3(RYR1):​c.6384C>T​(p.Tyr2128=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,612,800 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (15 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.24

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-38494461-C-T is Benign according to our data. Variant chr19-38494461-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38494461-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00567 (864/152344) while in subpopulation AFR AF= 0.0159 (659/41574). AF 95% confidence interval is 0.0148. There are 3 homozygotes in gnomad4. There are 408 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.6384C>T	p.Tyr2128=	synonymous_variant	39/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6384C>T	p.Tyr2128=	synonymous_variant	39/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.6384C>T	p.Tyr2128=	synonymous_variant	39/105	1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.6384C>T	p.Tyr2128=	synonymous_variant, NMD_transcript_variant	39/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 855 AN: 152226 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00103

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00286 AC: 715 AN: 250226 Hom.: 1 AF XY: 0.00275 AC XY: 373 AN XY: 135548

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00558

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.000839

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00222 AC: 3246 AN: 1460456 Hom.: 15 Cov.: 32 AF XY: 0.00220 AC XY: 1595 AN XY: 726568

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00224

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00317

GnomAD4 genome AF: 0.00567 AC: 864 AN: 152344 Hom.: 3 Cov.: 31 AF XY: 0.00548 AC XY: 408 AN XY: 74496

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00103

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00403 Hom.: 2

Bravo AF: 0.00624

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00308

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	Apr 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 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. -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Malignant hyperthermia, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

- -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.33
DANN	Benign	0.94

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: rs75181912; hg19: chr19-38985101;