rs61739895

Variant names:

• chr19-38561418-C-T
• rs61739895
• NM_000540.3:c.12588C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38561418-C-T
• chr19-38561418-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000540.3(RYR1):​c.12588C>T​(p.Ile4196Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000784 in 1,612,014 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene RYR1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (8 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.75
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 19-38561418-C-T is Benign according to our data. Variant chr19-38561418-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212092.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00433 (659/152354) while in subpopulation AFR AF = 0.015 (622/41578). AF 95% confidence interval is 0.014. There are 4 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.12588C>T	p.Ile4196Ile	synonymous	Exon 90 of 106	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.12573C>T	p.Ile4191Ile	synonymous	Exon 89 of 105	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.12588C>T	p.Ile4196Ile	synonymous	Exon 90 of 106	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.12573C>T	p.Ile4191Ile	synonymous	Exon 89 of 105	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*3298C>T		non_coding_transcript_exon	Exon 87 of 103	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 649 AN: 152236 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

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: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00113 AC: 280 AN: 247184 AF XY: 0.000723

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000414 AC: 605 AN: 1459660 Hom.: 8 Cov.: 34 AF XY: 0.000332 AC XY: 241 AN XY: 726200

African (AFR) AF: 0.0143 AC: 478 AN: 33474

American (AMR) AF: 0.000895 AC: 40 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111800

Other (OTH) AF: 0.00128 AC: 77 AN: 60360

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152354 Hom.: 4 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74504

African (AFR) AF: 0.0150 AC: 622 AN: 41578

American (AMR) AF: 0.00209 AC: 32 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00321 Hom.: 1

Bravo AF: 0.00502

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	2	Malignant hyperthermia, susceptibility to, 1 (2)
-	-	1	Central core myopathy (1)
-	-	1	Malignant hyperthermia of anesthesia (1)
-	-	1	Multiminicore myopathy (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	-0.27
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

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: rs61739895; hg19: chr19-39052058;