19-38527640-C-T

Variant names:

• chr19-38527640-C-T
• rs2960354
• NM_000540.3:c.10687-7C>T

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.10687-7C>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 0.058 in 1,613,818 control chromosomes in the GnomAD database, including 4,971 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 0.12 (1793 hom., cov: 31)
  • Exomes 𝑓: 0.052 (3178 hom.)
• Consequence: RYR1 NM_000540.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002812
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12 O:1
• Conservation: PhyloP100: 0.236
• Publications: 15 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

ENSG00000269445 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-38527640-C-T is Benign according to our data. Variant chr19-38527640-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 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.10687-7C>T		splice_region intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10672-7C>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.10687-7C>T		splice_region intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.10672-7C>T		splice_region intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*1415-7C>T		splice_region intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17873 AN: 152086 Hom.: 1785 Cov.: 31

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0522

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.0675 AC: 16893 AN: 250186 AF XY: 0.0627

Gnomad AFR exome AF: 0.280

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0885

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0517

Gnomad OTH exome AF: 0.0697

GnomAD4 exome AF: 0.0518 AC: 75674 AN: 1461614 Hom.: 3178 Cov.: 33 AF XY: 0.0511 AC XY: 37175 AN XY: 727088

African (AFR) AF: 0.275 AC: 9222 AN: 33474

American (AMR) AF: 0.0486 AC: 2170 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0920 AC: 2405 AN: 26128

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39692

South Asian (SAS) AF: 0.0361 AC: 3113 AN: 86210

European-Finnish (FIN) AF: 0.115 AC: 6134 AN: 53336

Middle Eastern (MID) AF: 0.0926 AC: 534 AN: 5768

European-Non Finnish (NFE) AF: 0.0433 AC: 48165 AN: 1111934

Other (OTH) AF: 0.0650 AC: 3923 AN: 60384

GnomAD4 genome AF: 0.118 AC: 17910 AN: 152204 Hom.: 1793 Cov.: 31 AF XY: 0.120 AC XY: 8934 AN XY: 74420

African (AFR) AF: 0.269 AC: 11156 AN: 41486

American (AMR) AF: 0.0775 AC: 1186 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0948 AC: 329 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4826

European-Finnish (FIN) AF: 0.118 AC: 1255 AN: 10608

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0521 AC: 3546 AN: 68014

Other (OTH) AF: 0.104 AC: 221 AN: 2116

Alfa AF: 0.0702 Hom.: 1248

Bravo AF: 0.123

Asia WGS AF: 0.0350 AC: 124 AN: 3478

EpiCase AF: 0.0575

EpiControl AF: 0.0551

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	1	1	not provided (3)
-	-	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	-0.75
CADD	Benign	12
DANN	Benign	0.58
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.026
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: rs2960354; hg19: chr19-39018280;