rs73930595

Variant names:

• chr19-38496377-A-G
• rs73930595
• NM_000540.3:c.6664-32A>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.6664-32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,613,678 control chromosomes in the GnomAD database, including 1,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (475 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1147 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.515
• Publications: 4 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=-0.78).
• BP6: Variant 19-38496377-A-G is Benign according to our data. Variant chr19-38496377-A-G is described in ClinVar as Benign. ClinVar VariationId is 256539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.6664-32A>G		intron_variant	Intron 40 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6664-32A>G		intron_variant	Intron 40 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8822 AN: 152120 Hom.: 473 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0325 AC: 8146 AN: 250712 AF XY: 0.0298

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0661

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0255

GnomAD4 exome AF: 0.0335 AC: 48964 AN: 1461440 Hom.: 1147 Cov.: 32 AF XY: 0.0324 AC XY: 23538 AN XY: 727020

African (AFR) AF: 0.136 AC: 4549 AN: 33480

American (AMR) AF: 0.0176 AC: 788 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 500 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00910 AC: 785 AN: 86256

European-Finnish (FIN) AF: 0.0629 AC: 3332 AN: 52994

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5768

European-Non Finnish (NFE) AF: 0.0331 AC: 36829 AN: 1111994

Other (OTH) AF: 0.0350 AC: 2115 AN: 60388

GnomAD4 genome AF: 0.0580 AC: 8837 AN: 152238 Hom.: 475 Cov.: 32 AF XY: 0.0583 AC XY: 4340 AN XY: 74438

African (AFR) AF: 0.136 AC: 5630 AN: 41536

American (AMR) AF: 0.0235 AC: 359 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4820

European-Finnish (FIN) AF: 0.0688 AC: 730 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0280 AC: 1906 AN: 68002

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0355 Hom.: 46

Bravo AF: 0.0582

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Oct 24, 2013

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.1
DANN	Benign	0.71
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs73930595; hg19: chr19-38987017;