chr19-38501000-C-G

Variant names:

• chr19-38501000-C-G
• rs2960323
• NM_000540.3:c.7614+10C>G

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.7614+10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,610,936 control chromosomes in the GnomAD database, including 29,684 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 0.23 (4562 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25122 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:16 O:1
• Conservation: PhyloP100: 0.348
• Publications: 9 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=-0.73).
• BP6: Variant 19-38501000-C-G is Benign according to our data. Variant chr19-38501000-C-G is described in ClinVar as Benign. ClinVar VariationId is 93289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.336 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.7614+10C>G		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.7614+10C>G		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.7614+10C>G		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.7614+10C>G		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.7614+10C>G		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35106 AN: 152002 Hom.: 4546 Cov.: 32

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.214 AC: 51936 AN: 242586 AF XY: 0.209

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.179 AC: 261471 AN: 1458818 Hom.: 25122 Cov.: 39 AF XY: 0.180 AC XY: 130547 AN XY: 725520

African (AFR) AF: 0.344 AC: 11494 AN: 33448

American (AMR) AF: 0.298 AC: 13241 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 4762 AN: 25990

East Asian (EAS) AF: 0.199 AC: 7885 AN: 39672

South Asian (SAS) AF: 0.215 AC: 18476 AN: 85856

European-Finnish (FIN) AF: 0.234 AC: 12271 AN: 52480

Middle Eastern (MID) AF: 0.205 AC: 1172 AN: 5714

European-Non Finnish (NFE) AF: 0.162 AC: 180429 AN: 1110962

Other (OTH) AF: 0.195 AC: 11741 AN: 60278

GnomAD4 genome AF: 0.231 AC: 35156 AN: 152118 Hom.: 4562 Cov.: 32 AF XY: 0.235 AC XY: 17501 AN XY: 74354

African (AFR) AF: 0.341 AC: 14123 AN: 41476

American (AMR) AF: 0.254 AC: 3877 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3472

East Asian (EAS) AF: 0.211 AC: 1091 AN: 5170

South Asian (SAS) AF: 0.218 AC: 1050 AN: 4822

European-Finnish (FIN) AF: 0.232 AC: 2456 AN: 10588

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11316 AN: 67984

Other (OTH) AF: 0.234 AC: 494 AN: 2110

Alfa AF: 0.125 Hom.: 281

Bravo AF: 0.239

Asia WGS AF: 0.249 AC: 867 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Central core myopathy (2)
-	-	2	Congenital multicore myopathy with external ophthalmoplegia (2)
-	1	1	not provided (3)
-	-	1	King Denborough syndrome (1)
-	-	1	Malignant hyperthermia, susceptibility to, 1 (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	-0.73
CADD	Benign	6.6
DANN	Benign	0.67
PhyloP100		0.35
Mutation Taster		=100/0	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: rs2960323; hg19: chr19-38991640; COSMIC: COSV62101652;