rs189170845

Variant names:

• chr19-38496170-C-T
• rs189170845
• NM_000540.3:c.6549-45C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000540.3(RYR1):​c.6549-45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,543,930 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00085 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (9 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.982
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 19-38496170-C-T is Benign according to our data. Variant chr19-38496170-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256536.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.6549-45C>T		intron_variant	Intron 39 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6549-45C>T		intron_variant	Intron 39 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00170 AC: 417 AN: 245694 AF XY: 0.00170

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.000972

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.000908 AC: 1263 AN: 1391644 Hom.: 9 Cov.: 24 AF XY: 0.000957 AC XY: 666 AN XY: 696144

African (AFR) AF: 0.00 AC: 0 AN: 32060

American (AMR) AF: 0.0000448 AC: 2 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 613 AN: 25726

East Asian (EAS) AF: 0.000229 AC: 9 AN: 39362

South Asian (SAS) AF: 0.000153 AC: 13 AN: 84730

European-Finnish (FIN) AF: 0.00168 AC: 83 AN: 49328

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5652

European-Non Finnish (NFE) AF: 0.000325 AC: 342 AN: 1051956

Other (OTH) AF: 0.00344 AC: 200 AN: 58204

GnomAD4 genome AF: 0.000854 AC: 130 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74462

African (AFR) AF: 0.000168 AC: 7 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00449 Hom.: 4

Bravo AF: 0.000979

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.089
DANN	Benign	0.81
PhyloP100		-0.98
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: rs189170845; hg19: chr19-38986810;