NM_000540.3:c.7615-7G>A

Variant names:

• chr19-38502500-G-A
• rs146159174
• NM_000540.3:c.7615-7G>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.7615-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000874 in 1,603,402 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (6 hom., cov: 29)
  • Exomes 𝑓: 0.00047 (7 hom.)
• Consequence: RYR1 NM_000540.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001181
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.26
• Publications: 1 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=-0.86).
• BP6: Variant 19-38502500-G-A is Benign according to our data. Variant chr19-38502500-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00475 (719/151226) while in subpopulation AFR AF = 0.017 (700/41090). AF 95% confidence interval is 0.016. There are 6 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.7615-7G>A		splice_region intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.7615-7G>A		splice_region intron	N/A	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.7615-7G>A		splice_region intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.7615-7G>A		splice_region intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.7615-7G>A		splice_region intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 719 AN: 151110 Hom.: 6 Cov.: 29

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.00133 AC: 319 AN: 239964 AF XY: 0.000936

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.000706

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.000847

GnomAD4 exome AF: 0.000470 AC: 682 AN: 1452176 Hom.: 7 Cov.: 36 AF XY: 0.000400 AC XY: 289 AN XY: 722154

African (AFR) AF: 0.0165 AC: 552 AN: 33402

American (AMR) AF: 0.000857 AC: 38 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47516

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5604

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1110412

Other (OTH) AF: 0.000931 AC: 56 AN: 60182

GnomAD4 genome AF: 0.00475 AC: 719 AN: 151226 Hom.: 6 Cov.: 29 AF XY: 0.00455 AC XY: 336 AN XY: 73902

African (AFR) AF: 0.0170 AC: 700 AN: 41090

American (AMR) AF: 0.00112 AC: 17 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67758

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.00328 Hom.: 1

Bravo AF: 0.00561

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Central core myopathy (1)
-	-	1	Malignant hyperthermia of anesthesia (1)
-	-	1	Malignant hyperthermia, susceptibility to, 1 (1)
-	-	1	Multiminicore myopathy (1)
-	-	1	Neuromuscular disease, congenital, with uniform type 1 fiber (1)
-	-	1	not provided (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.066
DANN	Benign	0.44
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0
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: rs146159174; hg19: chr19-38993140;