chr19-38448865-T-C

Variant names:

• chr19-38448865-T-C
• rs4476278
• NM_000540.3:c.1122+52T>C

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.1122+52T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.979 in 1,564,548 control chromosomes in the GnomAD database, including 750,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74047 hom., cov: 30)
  • Exomes 𝑓: 0.98 (676133 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.554
• 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), 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=-1.0).
• BP6: Variant 19-38448865-T-C is Benign according to our data. Variant chr19-38448865-T-C is described in ClinVar as Benign. ClinVar VariationId is 133008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.1122+52T>C		intron_variant	Intron 11 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.1122+52T>C		intron_variant	Intron 11 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.986 AC: 150031 AN: 152124 Hom.: 73991 Cov.: 30

Gnomad AFR AF: 0.996

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 0.989

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.978

Gnomad FIN AF: 0.989

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.977

Gnomad OTH AF: 0.988

GnomAD2 exomes AF: 0.984 AC: 209315 AN: 212674 AF XY: 0.983

Gnomad AFR exome AF: 0.995

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 0.988

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.988

Gnomad NFE exome AF: 0.978

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.978 AC: 1381870 AN: 1412306 Hom.: 676133 Cov.: 23 AF XY: 0.979 AC XY: 687821 AN XY: 702928

African (AFR) AF: 0.996 AC: 32419 AN: 32546

American (AMR) AF: 0.995 AC: 40192 AN: 40400

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 25146 AN: 25462

East Asian (EAS) AF: 1.00 AC: 38497 AN: 38498

South Asian (SAS) AF: 0.974 AC: 81760 AN: 83916

European-Finnish (FIN) AF: 0.988 AC: 49256 AN: 49872

Middle Eastern (MID) AF: 0.997 AC: 4317 AN: 4332

European-Non Finnish (NFE) AF: 0.976 AC: 1052679 AN: 1078666

Other (OTH) AF: 0.983 AC: 57604 AN: 58614

GnomAD4 genome AF: 0.986 AC: 150146 AN: 152242 Hom.: 74047 Cov.: 30 AF XY: 0.987 AC XY: 73479 AN XY: 74442

African (AFR) AF: 0.996 AC: 41379 AN: 41546

American (AMR) AF: 0.994 AC: 15204 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 3433 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5148 AN: 5150

South Asian (SAS) AF: 0.978 AC: 4718 AN: 4824

European-Finnish (FIN) AF: 0.989 AC: 10497 AN: 10610

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.977 AC: 66476 AN: 68024

Other (OTH) AF: 0.988 AC: 2085 AN: 2110

Alfa AF: 0.983 Hom.: 13465

Bravo AF: 0.987

Asia WGS AF: 0.992 AC: 3451 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.2
DANN	Benign	0.30
PhyloP100		-0.55
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: rs4476278; hg19: chr19-38939505;