rs199849275

Variant names:

• chr19-38502851-G-GA
• rs199849275
• NM_000540.3:c.7836-28dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000540.3(RYR1):​c.7836-28dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,600,600 control chromosomes in the GnomAD database, including 267 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 29)
  • Exomes 𝑓: 0.014 (253 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.62
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 19-38502851-G-GA is Benign according to our data. Variant chr19-38502851-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 256561.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1653/151022) while in subpopulation NFE AF = 0.0172 (1162/67616). AF 95% confidence interval is 0.0164. There are 14 homozygotes in GnomAd4. There are 751 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7836-28dupA		intron_variant	Intron 48 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7836-29_7836-28insA		intron_variant	Intron 48 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1653 AN: 150908 Hom.: 14 Cov.: 29

Gnomad AFR AF: 0.00312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00337

Gnomad FIN AF: 0.00803

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0111

GnomAD2 exomes AF: 0.00918 AC: 2221 AN: 241952 AF XY: 0.00950

Gnomad AFR exome AF: 0.00220

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00624

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.0136 AC: 19697 AN: 1449578 Hom.: 253 Cov.: 33 AF XY: 0.0134 AC XY: 9658 AN XY: 721456

African (AFR) AF: 0.00215 AC: 72 AN: 33412

American (AMR) AF: 0.00944 AC: 421 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 348 AN: 26078

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39672

South Asian (SAS) AF: 0.00309 AC: 265 AN: 85890

European-Finnish (FIN) AF: 0.00876 AC: 407 AN: 46462

Middle Eastern (MID) AF: 0.00560 AC: 32 AN: 5716

European-Non Finnish (NFE) AF: 0.0157 AC: 17376 AN: 1107574

Other (OTH) AF: 0.0128 AC: 772 AN: 60154

GnomAD4 genome AF: 0.0109 AC: 1653 AN: 151022 Hom.: 14 Cov.: 29 AF XY: 0.0102 AC XY: 751 AN XY: 73756

African (AFR) AF: 0.00311 AC: 128 AN: 41180

American (AMR) AF: 0.0116 AC: 176 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3460

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5100

South Asian (SAS) AF: 0.00358 AC: 17 AN: 4742

European-Finnish (FIN) AF: 0.00803 AC: 84 AN: 10460

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0172 AC: 1162 AN: 67616

Other (OTH) AF: 0.0110 AC: 23 AN: 2094

Alfa AF: 0.00759 Hom.: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism

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: rs199849275; hg19: chr19-38993491;