chr19-38528513-A-G

Variant names:

• chr19-38528513-A-G
• rs6508806
• NM_000540.3:c.10938-86A>G

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.10938-86A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,589,218 control chromosomes in the GnomAD database, including 21,338 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1907 hom., cov: 31)
  • Exomes 𝑓: 0.16 (19431 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.675
• Publications: 7 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=-0.9).
• BP6: Variant 19-38528513-A-G is Benign according to our data. Variant chr19-38528513-A-G is described in ClinVar as Benign. ClinVar VariationId is 133002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 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.10938-86A>G		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.10923-86A>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.10938-86A>G		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.10923-86A>G		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.*1666-86A>G		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22880 AN: 151860 Hom.: 1896 Cov.: 31

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.158

GnomAD4 exome AF: 0.156 AC: 224574 AN: 1437240 Hom.: 19431 Cov.: 27 AF XY: 0.159 AC XY: 114209 AN XY: 716108

African (AFR) AF: 0.119 AC: 3943 AN: 33060

American (AMR) AF: 0.281 AC: 12363 AN: 43996

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2898 AN: 25948

East Asian (EAS) AF: 0.220 AC: 8687 AN: 39532

South Asian (SAS) AF: 0.287 AC: 24549 AN: 85592

European-Finnish (FIN) AF: 0.142 AC: 7549 AN: 53238

Middle Eastern (MID) AF: 0.161 AC: 906 AN: 5628

European-Non Finnish (NFE) AF: 0.141 AC: 154144 AN: 1090640

Other (OTH) AF: 0.160 AC: 9535 AN: 59606

GnomAD4 genome AF: 0.151 AC: 22930 AN: 151978 Hom.: 1907 Cov.: 31 AF XY: 0.154 AC XY: 11436 AN XY: 74284

African (AFR) AF: 0.120 AC: 4958 AN: 41472

American (AMR) AF: 0.225 AC: 3430 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3468

East Asian (EAS) AF: 0.236 AC: 1209 AN: 5132

South Asian (SAS) AF: 0.302 AC: 1453 AN: 4818

European-Finnish (FIN) AF: 0.124 AC: 1317 AN: 10584

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.141 AC: 9589 AN: 67938

Other (OTH) AF: 0.163 AC: 343 AN: 2108

Alfa AF: 0.0590 Hom.: 66

Bravo AF: 0.153

Asia WGS AF: 0.324 AC: 1124 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.52
DANN	Benign	0.28
PhyloP100		-0.68
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: rs6508806; hg19: chr19-39019153; COSMIC: COSV62103830; COSMIC: COSV62103830;