rs2960343

Variant names:

• chr19-38505983-T-G
• rs2960343
• NM_000540.3:c.8541+37T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-38505983-T-G
• chr19-38505983-T-A
• chr19-38505983-T-C

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.8541+37T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,536,592 control chromosomes in the GnomAD database, including 64,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8425 hom., cov: 29)
  • Exomes 𝑓: 0.26 (55949 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.510
• Publications: 8 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-38505983-T-G is Benign according to our data. Variant chr19-38505983-T-G is described in ClinVar as Benign. ClinVar VariationId is 133228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.449 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.8541+37T>G		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8541+37T>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.8541+37T>G		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.8541+37T>G		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.8541+37T>G		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.329 AC: 48755 AN: 148026 Hom.: 8388 Cov.: 29

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.338

GnomAD2 exomes AF: 0.319 AC: 75963 AN: 238388 AF XY: 0.319

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.336

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.263 AC: 364531 AN: 1388446 Hom.: 55949 Cov.: 32 AF XY: 0.268 AC XY: 185762 AN XY: 692798

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.425 AC: 13469 AN: 31674

American (AMR) AF: 0.386 AC: 17059 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 6333 AN: 25634

East Asian (EAS) AF: 0.335 AC: 13103 AN: 39078

South Asian (SAS) AF: 0.442 AC: 37041 AN: 83728

European-Finnish (FIN) AF: 0.289 AC: 14550 AN: 50304

Middle Eastern (MID) AF: 0.316 AC: 1424 AN: 4510

European-Non Finnish (NFE) AF: 0.233 AC: 245134 AN: 1051468

Other (OTH) AF: 0.284 AC: 16418 AN: 57878

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.330 AC: 48854 AN: 148146 Hom.: 8425 Cov.: 29 AF XY: 0.338 AC XY: 24365 AN XY: 72140

African (AFR) AF: 0.438 AC: 17584 AN: 40192

American (AMR) AF: 0.357 AC: 5355 AN: 14984

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 879 AN: 3412

East Asian (EAS) AF: 0.363 AC: 1816 AN: 4996

South Asian (SAS) AF: 0.465 AC: 2180 AN: 4688

European-Finnish (FIN) AF: 0.297 AC: 2976 AN: 10012

Middle Eastern (MID) AF: 0.315 AC: 90 AN: 286

European-Non Finnish (NFE) AF: 0.256 AC: 17034 AN: 66638

Other (OTH) AF: 0.343 AC: 705 AN: 2054

Alfa AF: 0.193 Hom.: 607

Bravo AF: 0.333

Asia WGS AF: 0.484 AC: 1677 AN: 3470

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	-0.90
CADD	Benign	0.86
DANN	Benign	0.54
PhyloP100		-0.51
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: rs2960343; hg19: chr19-38996623; COSMIC: COSV62092767;