chr19-38543894-T-C

Variant names:

• chr19-38543894-T-C
• rs181590606
• NM_000540.3:c.12012+19T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):​c.12012+19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,608,598 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (10 hom., cov: 32)
  • Exomes 𝑓: 0.018 (268 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.728
• 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), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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=-0.79).
• BP6: Variant 19-38543894-T-C is Benign according to our data. Variant chr19-38543894-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1840/152290) while in subpopulation NFE AF = 0.0196 (1334/68012). AF 95% confidence interval is 0.0187. There are 10 homozygotes in GnomAd4. There are 831 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,AD 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.12012+19T>C		intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.11997+19T>C		intron	N/A	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.12012+19T>C		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.11997+19T>C		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*2722+19T>C		intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1840 AN: 152172 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.0125 AC: 3074 AN: 245052 AF XY: 0.0128

Gnomad AFR exome AF: 0.00325

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0181 AC: 26384 AN: 1456308 Hom.: 268 Cov.: 33 AF XY: 0.0176 AC XY: 12773 AN XY: 724366

African (AFR) AF: 0.00246 AC: 82 AN: 33368

American (AMR) AF: 0.00506 AC: 225 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 461 AN: 26066

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39638

South Asian (SAS) AF: 0.00486 AC: 417 AN: 85734

European-Finnish (FIN) AF: 0.0153 AC: 807 AN: 52866

Middle Eastern (MID) AF: 0.00151 AC: 7 AN: 4624

European-Non Finnish (NFE) AF: 0.0211 AC: 23370 AN: 1109436

Other (OTH) AF: 0.0168 AC: 1013 AN: 60138

GnomAD4 genome AF: 0.0121 AC: 1840 AN: 152290 Hom.: 10 Cov.: 32 AF XY: 0.0112 AC XY: 831 AN XY: 74474

African (AFR) AF: 0.00373 AC: 155 AN: 41558

American (AMR) AF: 0.00654 AC: 100 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4824

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0196 AC: 1334 AN: 68012

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.0153 Hom.: 17

Bravo AF: 0.0113

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
-	-	1	RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.6
DANN	Benign	0.70
PhyloP100		0.73
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: rs181590606; hg19: chr19-39034534;