rs2960344

Variant names:

• chr19-38506436-C-T
• rs2960344
• NM_000540.3:c.8617-35C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38506436-C-T
• chr19-38506436-C-A
• chr19-38506436-C-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.8617-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,613,498 control chromosomes in the GnomAD database, including 67,589 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 0.33 (8640 hom., cov: 31)
  • Exomes 𝑓: 0.28 (58949 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.191
• 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=-0.8).
• BP6: Variant 19-38506436-C-T is Benign according to our data. Variant chr19-38506436-C-T is described in ClinVar as Benign. ClinVar VariationId is 133231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 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.8617-35C>T		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8617-35C>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.8617-35C>T		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.8617-35C>T		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.8617-35C>T		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49485 AN: 151856 Hom.: 8604 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.322 AC: 80829 AN: 251312 AF XY: 0.321

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.256

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.276 AC: 403163 AN: 1461522 Hom.: 58949 Cov.: 36 AF XY: 0.280 AC XY: 203846 AN XY: 727080

African (AFR) AF: 0.433 AC: 14506 AN: 33476

American (AMR) AF: 0.388 AC: 17349 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6584 AN: 26132

East Asian (EAS) AF: 0.338 AC: 13421 AN: 39696

South Asian (SAS) AF: 0.447 AC: 38534 AN: 86258

European-Finnish (FIN) AF: 0.293 AC: 15640 AN: 53408

Middle Eastern (MID) AF: 0.338 AC: 1947 AN: 5768

European-Non Finnish (NFE) AF: 0.250 AC: 277431 AN: 1111678

Other (OTH) AF: 0.294 AC: 17751 AN: 60388

GnomAD4 genome AF: 0.326 AC: 49582 AN: 151976 Hom.: 8640 Cov.: 31 AF XY: 0.333 AC XY: 24770 AN XY: 74290

African (AFR) AF: 0.431 AC: 17870 AN: 41440

American (AMR) AF: 0.356 AC: 5439 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 893 AN: 3470

East Asian (EAS) AF: 0.362 AC: 1856 AN: 5132

South Asian (SAS) AF: 0.460 AC: 2212 AN: 4810

European-Finnish (FIN) AF: 0.290 AC: 3067 AN: 10586

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17207 AN: 67936

Other (OTH) AF: 0.337 AC: 709 AN: 2106

Alfa AF: 0.280 Hom.: 3199

Bravo AF: 0.333

Asia WGS AF: 0.487 AC: 1692 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Central core myopathy (1)
-	-	1	Congenital multicore myopathy with external ophthalmoplegia (1)
-	-	1	King Denborough syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.7
DANN	Benign	0.71
PhyloP100		0.19
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: rs2960344; hg19: chr19-38997076; COSMIC: COSV62092509;