rs147012990

Positions:

• chr19-38512253-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000540.3(RYR1):​c.9242T>C​(p.Met3081Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000367 in 1,614,246 control chromosomes in the GnomAD database, including 4 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 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 6.27

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.010569692).
• BP6: Variant 19-38512253-T-C is Benign according to our data. Variant chr19-38512253-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=3}. Variant chr19-38512253-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00193 (294/152352) while in subpopulation AFR AF= 0.00649 (270/41584). AF 95% confidence interval is 0.00586. There are 2 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.9242T>C	p.Met3081Thr	missense_variant	63/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.9242T>C	p.Met3081Thr	missense_variant	63/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.9242T>C	p.Met3081Thr	missense_variant	63/105	1		P4
RYR1	ENST00000594335.5	c.2646T>C	p.Asp882=	synonymous_variant, NMD_transcript_variant	23/49	1
RYR1	ENST00000599547.6	c.*1T>C		3_prime_UTR_variant, NMD_transcript_variant	62/80	2

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 293 AN: 152234 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.00239

GnomAD3 exomes AF: 0.000581 AC: 146 AN: 251394 Hom.: 0 AF XY: 0.000412 AC XY: 56 AN XY: 135918

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.000607

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: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000204 AC: 298 AN: 1461894 Hom.: 2 Cov.: 34 AF XY: 0.000154 AC XY: 112 AN XY: 727248

Gnomad4 AFR exome AF: 0.00684

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152352 Hom.: 2 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74512

Gnomad4 AFR AF: 0.00649

Gnomad4 AMR AF: 0.00105

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: 0.00237

Alfa AF: 0.000403 Hom.: 0

Bravo AF: 0.00221

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000659 AC: 80

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 08, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 18, 2022	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2024	Reported in two patients with congenital myopathies with central nuclei who also harbored other variants in the RYR1 gene (PMID: 20839240); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27855725, 27153395, 12668474, 20839240, 24195946) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 08, 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

Jun 14, 2016

- -

RYR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	20
DANN	Benign	0.87
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.19	T;T
Polyphen		0.76	P;P
Vest4		0.52
MVP		0.99
MPC		0.36
ClinPred		0.066	T
GERP RS		4.6
Varity_R		0.59
gMVP		0.61

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: rs147012990; hg19: chr19-39002893; COSMIC: COSV99052018;