19-38444710-TC-TCC

Variant names:

• chr19-38444710-T-TC
• rs35018208
• NM_000540.3:c.631+39dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.631+39dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,472,310 control chromosomes in the GnomAD database, including 280,875 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27655 hom., cov: 0)
  • Exomes 𝑓: 0.61 (253220 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.767
• Publications: 4 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 -16 ACMG points.

• BP6: Variant 19-38444710-T-TC is Benign according to our data. Variant chr19-38444710-T-TC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.664 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.631+39dupC		intron	N/A	NP_000531.2
	RYR1	NM_001042723.2		c.631+39dupC		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.631+33_631+34insC		intron	N/A	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.631+33_631+34insC		intron	N/A	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.631+33_631+34insC		intron	N/A	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.605 AC: 89718 AN: 148410 Hom.: 27649 Cov.: 0

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.749

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.622

GnomAD2 exomes AF: 0.596 AC: 127034 AN: 213030 AF XY: 0.588

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.672

Gnomad ASJ exome AF: 0.611

Gnomad EAS exome AF: 0.618

Gnomad FIN exome AF: 0.639

Gnomad NFE exome AF: 0.629

Gnomad OTH exome AF: 0.632

GnomAD4 exome AF: 0.610 AC: 808036 AN: 1323784 Hom.: 253220 Cov.: 21 AF XY: 0.605 AC XY: 400779 AN XY: 662900

African (AFR) AF: 0.499 AC: 15420 AN: 30904

American (AMR) AF: 0.668 AC: 27581 AN: 41266

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 15030 AN: 25038

East Asian (EAS) AF: 0.649 AC: 24468 AN: 37722

South Asian (SAS) AF: 0.407 AC: 33230 AN: 81734

European-Finnish (FIN) AF: 0.642 AC: 33307 AN: 51920

Middle Eastern (MID) AF: 0.611 AC: 3372 AN: 5520

European-Non Finnish (NFE) AF: 0.625 AC: 621492 AN: 993954

Other (OTH) AF: 0.613 AC: 34136 AN: 55726

GnomAD4 genome AF: 0.604 AC: 89757 AN: 148526 Hom.: 27655 Cov.: 0 AF XY: 0.600 AC XY: 43301 AN XY: 72204

African (AFR) AF: 0.517 AC: 20718 AN: 40072

American (AMR) AF: 0.675 AC: 10062 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2122 AN: 3458

East Asian (EAS) AF: 0.623 AC: 3070 AN: 4928

South Asian (SAS) AF: 0.405 AC: 1893 AN: 4678

European-Finnish (FIN) AF: 0.652 AC: 6427 AN: 9858

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.643 AC: 43330 AN: 67368

Other (OTH) AF: 0.615 AC: 1274 AN: 2070

Alfa AF: 0.556 Hom.: 2967

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Oct 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

King Denborough syndrome Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Central core myopathy Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.77
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: rs35018208; hg19: chr19-38935350;