chr19-38494668-G-A

Variant names:

• chr19-38494668-G-A
• rs75563090
• NM_000540.3:c.6548+43G>A

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.6548+43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.036 in 1,609,796 control chromosomes in the GnomAD database, including 1,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (173 hom., cov: 31)
  • Exomes 𝑓: 0.036 (1196 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.60
• Publications: 6 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=-0.92).
• BP6: Variant 19-38494668-G-A is Benign according to our data. Variant chr19-38494668-G-A is described in ClinVar as Benign. ClinVar VariationId is 256535.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 = 0.0385 (5863/152110) while in subpopulation NFE AF = 0.0405 (2750/67974). AF 95% confidence interval is 0.0392. There are 173 homozygotes in GnomAd4. There are 3102 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 173 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.6548+43G>A		intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.6548+43G>A		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.6548+43G>A		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.6548+43G>A		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.6548+43G>A		intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 5860 AN: 151992 Hom.: 173 Cov.: 31

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0394

GnomAD2 exomes AF: 0.0392 AC: 9667 AN: 246584 AF XY: 0.0386

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0502

Gnomad EAS exome AF: 0.0134

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0399

Gnomad OTH exome AF: 0.0431

GnomAD4 exome AF: 0.0357 AC: 52065 AN: 1457686 Hom.: 1196 Cov.: 30 AF XY: 0.0355 AC XY: 25755 AN XY: 725364

African (AFR) AF: 0.0250 AC: 836 AN: 33392

American (AMR) AF: 0.0196 AC: 875 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 1364 AN: 26116

East Asian (EAS) AF: 0.00847 AC: 336 AN: 39684

South Asian (SAS) AF: 0.0216 AC: 1864 AN: 86154

European-Finnish (FIN) AF: 0.114 AC: 6000 AN: 52734

Middle Eastern (MID) AF: 0.0387 AC: 221 AN: 5708

European-Non Finnish (NFE) AF: 0.0347 AC: 38485 AN: 1108924

Other (OTH) AF: 0.0346 AC: 2084 AN: 60254

GnomAD4 genome AF: 0.0385 AC: 5863 AN: 152110 Hom.: 173 Cov.: 31 AF XY: 0.0417 AC XY: 3102 AN XY: 74370

African (AFR) AF: 0.0231 AC: 959 AN: 41498

American (AMR) AF: 0.0281 AC: 429 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 190 AN: 3470

East Asian (EAS) AF: 0.0148 AC: 77 AN: 5186

South Asian (SAS) AF: 0.0187 AC: 90 AN: 4820

European-Finnish (FIN) AF: 0.117 AC: 1239 AN: 10572

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0405 AC: 2750 AN: 67974

Other (OTH) AF: 0.0390 AC: 82 AN: 2104

Alfa AF: 0.0407 Hom.: 43

Bravo AF: 0.0321

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.43
DANN	Benign	0.56
PhyloP100		-1.6
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: rs75563090; hg19: chr19-38985308; COSMIC: COSV107443182; COSMIC: COSV107443182;