rs2960337

Variant names:

• chr19-38511974-T-G
• rs2960337
• NM_000540.3:c.9173-98T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.9173-98T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,384,122 control chromosomes in the GnomAD database, including 25,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3718 hom., cov: 31)
  • Exomes 𝑓: 0.17 (21581 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.660
• Publications: 9 publications found

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]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-38511974-T-G is Benign according to our data. Variant chr19-38511974-T-G is described in ClinVar as Benign. ClinVar VariationId is 133239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.9173-98T>G		intron_variant	Intron 61 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.9173-98T>G		intron_variant	Intron 61 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31752 AN: 151796 Hom.: 3698 Cov.: 31

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.175 AC: 215140 AN: 1232208 Hom.: 21581 AF XY: 0.180 AC XY: 111316 AN XY: 617016

African (AFR) AF: 0.270 AC: 7492 AN: 27786

American (AMR) AF: 0.299 AC: 10892 AN: 36416

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 3266 AN: 24134

East Asian (EAS) AF: 0.208 AC: 7468 AN: 35856

South Asian (SAS) AF: 0.366 AC: 27945 AN: 76362

European-Finnish (FIN) AF: 0.165 AC: 8172 AN: 49652

Middle Eastern (MID) AF: 0.201 AC: 1065 AN: 5298

European-Non Finnish (NFE) AF: 0.150 AC: 139073 AN: 924290

Other (OTH) AF: 0.186 AC: 9767 AN: 52414

GnomAD4 genome AF: 0.209 AC: 31821 AN: 151914 Hom.: 3718 Cov.: 31 AF XY: 0.214 AC XY: 15866 AN XY: 74250

African (AFR) AF: 0.283 AC: 11709 AN: 41410

American (AMR) AF: 0.244 AC: 3719 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3466

East Asian (EAS) AF: 0.220 AC: 1131 AN: 5142

South Asian (SAS) AF: 0.384 AC: 1849 AN: 4816

European-Finnish (FIN) AF: 0.162 AC: 1713 AN: 10570

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10637 AN: 67938

Other (OTH) AF: 0.217 AC: 458 AN: 2114

Alfa AF: 0.177 Hom.: 10658

Bravo AF: 0.216

Asia WGS AF: 0.362 AC: 1257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.5
DANN	Benign	0.66
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2960337; hg19: chr19-39002614;