rs45585535

Variant names:

• chr19-38466086-C-T
• rs45585535
• NM_000540.3:c.2871-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38466086-C-T
• chr19-38466086-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):​c.2871-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,605,616 control chromosomes in the GnomAD database, including 1,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). The gene RYR1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.030 (136 hom., cov: 32)
  • Exomes 𝑓: 0.032 (986 hom.)
• Consequence: RYR1 NM_000540.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001598
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.857
• Publications: 7 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=-0.81).
• BP6: Variant 19-38466086-C-T is Benign according to our data. Variant chr19-38466086-C-T is described in ClinVar as Benign. ClinVar VariationId is 93260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.03 (4566/152264) while in subpopulation NFE AF = 0.0377 (2563/68012). AF 95% confidence interval is 0.0365. There are 136 homozygotes in GnomAd4. There are 2473 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 136 AD,AR gene

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.2871-5C>T		splice_region intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.2871-5C>T		splice_region 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.2871-5C>T		splice_region intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.2871-5C>T		splice_region intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.2871-5C>T		splice_region intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4569 AN: 152146 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0267

GnomAD2 exomes AF: 0.0307 AC: 7110 AN: 231340 AF XY: 0.0301

Gnomad AFR exome AF: 0.00463

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0357

Gnomad OTH exome AF: 0.0338

GnomAD4 exome AF: 0.0316 AC: 45921 AN: 1453352 Hom.: 986 Cov.: 30 AF XY: 0.0312 AC XY: 22509 AN XY: 722488

African (AFR) AF: 0.00415 AC: 138 AN: 33282

American (AMR) AF: 0.0132 AC: 579 AN: 43772

Ashkenazi Jewish (ASJ) AF: 0.0393 AC: 1020 AN: 25952

East Asian (EAS) AF: 0.0000766 AC: 3 AN: 39158

South Asian (SAS) AF: 0.00875 AC: 743 AN: 84936

European-Finnish (FIN) AF: 0.109 AC: 5681 AN: 51938

Middle Eastern (MID) AF: 0.0207 AC: 119 AN: 5756

European-Non Finnish (NFE) AF: 0.0325 AC: 35988 AN: 1108536

Other (OTH) AF: 0.0275 AC: 1650 AN: 60022

GnomAD4 genome AF: 0.0300 AC: 4566 AN: 152264 Hom.: 136 Cov.: 32 AF XY: 0.0332 AC XY: 2473 AN XY: 74442

African (AFR) AF: 0.00513 AC: 213 AN: 41558

American (AMR) AF: 0.0192 AC: 294 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 138 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00954 AC: 46 AN: 4824

European-Finnish (FIN) AF: 0.115 AC: 1220 AN: 10592

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0377 AC: 2563 AN: 68012

Other (OTH) AF: 0.0265 AC: 56 AN: 2116

Alfa AF: 0.0326 Hom.: 207

Bravo AF: 0.0224

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	Neuromuscular disease, congenital, with uniform type 1 fiber (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.87
DANN	Benign	0.78
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0020
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: rs45585535; hg19: chr19-38956726;