19-38499306-G-A

Variant names:

• chr19-38499306-G-A
• rs3745852
• NM_000540.3:c.7027+63G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000540.3(RYR1):​c.7027+63G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,611,672 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0075 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (200 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.86
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7027+63G>A		intron_variant	Intron 43 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7027+63G>A		intron_variant	Intron 43 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1148 AN: 152192 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0689

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.00493 AC: 7195 AN: 1459362 Hom.: 200 AF XY: 0.00522 AC XY: 3787 AN XY: 726108

African (AFR) AF: 0.000538 AC: 18 AN: 33438

American (AMR) AF: 0.0409 AC: 1828 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26126

East Asian (EAS) AF: 0.0729 AC: 2891 AN: 39682

South Asian (SAS) AF: 0.0203 AC: 1753 AN: 86146

European-Finnish (FIN) AF: 0.000358 AC: 19 AN: 53006

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5758

European-Non Finnish (NFE) AF: 0.000177 AC: 196 AN: 1110176

Other (OTH) AF: 0.00718 AC: 433 AN: 60320

GnomAD4 genome AF: 0.00754 AC: 1148 AN: 152310 Hom.: 31 Cov.: 32 AF XY: 0.00924 AC XY: 688 AN XY: 74466

African (AFR) AF: 0.00139 AC: 58 AN: 41586

American (AMR) AF: 0.0365 AC: 558 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.0689 AC: 357 AN: 5184

South Asian (SAS) AF: 0.0263 AC: 127 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68006

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00321 Hom.: 11

Bravo AF: 0.00997

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.055
DANN	Benign	0.68
PhyloP100		-1.9
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: rs3745852; hg19: chr19-38989946; COSMIC: COSV62088010;