rs2960341

Variant names:

• chr19-38505459-C-T
• rs2960341
• NM_000540.3:c.8400+61C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38505459-C-T
• chr19-38505459-C-A

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.8400+61C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,224,474 control chromosomes in the GnomAD database, including 1,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene RYR1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.069 (700 hom., cov: 31)
  • Exomes 𝑓: 0.033 (989 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.262
• Publications: 3 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), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, ClinGen
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), 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

Specifications for RYR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-38505459-C-T is Benign according to our data. Variant chr19-38505459-C-T is described in ClinVar as Benign. ClinVar VariationId is 133225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.8400+61C>T		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8400+61C>T		intron	N/A	NP_001036188.1	P21817-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.8400+61C>T		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.8400+61C>T		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.8400+61C>T		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10482 AN: 152100 Hom.: 696 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00913

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0618

GnomAD4 exome AF: 0.0333 AC: 35750 AN: 1072256 Hom.: 989 AF XY: 0.0322 AC XY: 17511 AN XY: 543944

African (AFR) AF: 0.164 AC: 4097 AN: 25004

American (AMR) AF: 0.0885 AC: 3180 AN: 35938

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 665 AN: 23250

East Asian (EAS) AF: 0.0000863 AC: 3 AN: 34754

South Asian (SAS) AF: 0.0205 AC: 1500 AN: 73198

European-Finnish (FIN) AF: 0.0135 AC: 659 AN: 48866

Middle Eastern (MID) AF: 0.0284 AC: 140 AN: 4928

European-Non Finnish (NFE) AF: 0.0303 AC: 23606 AN: 778994

Other (OTH) AF: 0.0401 AC: 1900 AN: 47324

GnomAD4 genome AF: 0.0691 AC: 10522 AN: 152218 Hom.: 700 Cov.: 31 AF XY: 0.0671 AC XY: 4998 AN XY: 74444

African (AFR) AF: 0.168 AC: 6973 AN: 41510

American (AMR) AF: 0.0714 AC: 1091 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4816

European-Finnish (FIN) AF: 0.00913 AC: 97 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2029 AN: 68006

Other (OTH) AF: 0.0611 AC: 129 AN: 2110

Alfa AF: 0.0519 Hom.: 57

Bravo AF: 0.0799

Asia WGS AF: 0.0220 AC: 78 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.3
DANN	Benign	0.53
PhyloP100		-0.26
Mutation Taster		=98/2	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: rs2960341; hg19: chr19-38996099; COSMIC: COSV62114020;