rs142558977

Positions:

• chr19-38502967-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000540.3(RYR1):​c.7923C>G​(p.Leu2641=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,608,840 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (3 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -0.0390

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-38502967-C-G is Benign according to our data. Variant chr19-38502967-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197609.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, Benign=3}. Variant chr19-38502967-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.039 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7923C>G	p.Leu2641=	synonymous_variant	49/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7923C>G	p.Leu2641=	synonymous_variant	49/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7923C>G	p.Leu2641=	synonymous_variant	49/105	1		P4
RYR1	ENST00000594335.5	c.1377C>G	p.Leu459=	synonymous_variant, NMD_transcript_variant	10/49	1
RYR1	ENST00000599547.6	c.7923C>G	p.Leu2641=	synonymous_variant, NMD_transcript_variant	49/80	2

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00109 AC: 270 AN: 247154 Hom.: 0 AF XY: 0.00108 AC XY: 144 AN XY: 133922

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00244

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000856 AC: 1247 AN: 1456566 Hom.: 3 Cov.: 37 AF XY: 0.000909 AC XY: 659 AN XY: 724762

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00185

Gnomad4 NFE exome AF: 0.000909

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74452

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00263 Hom.: 0

Bravo AF: 0.000933

EpiCase AF: 0.00115

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RYR1: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2020	This variant is associated with the following publications: (PMID: 20681998) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Malignant hyperthermia, susceptibility to, 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 03, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 03, 2018

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. -

Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 03, 2018

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. -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.8
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: rs142558977; hg19: chr19-38993607;