Genetic Variant RYR1:c.1122+52T>C (chr19-38448865-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: -0.554

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 133008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38448865-T-C is described in Lovd as [Benign].

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 link	c.1122+52T>C		intron_variant	Intron 11 of 105	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.1122+52T>C	intron_variant	Intron 11 of 105	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.1122+52T>C	intron_variant	Intron 11 of 104	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 link	n.1122+52T>C	intron_variant	Intron 11 of 79	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.986

AC:

150031

AN:

152124

Hom.:

73991

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.984

AC:

209315

AN:

212674

Hom.:

103022

AF XY:

0.983

AC XY:

113571

AN XY:

115528

show subpopulations

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 SAS exome

AF:

0.976

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.:

AF XY:

0.979

AC XY:

687821

AN XY:

702928

show subpopulations

Gnomad4 AFR exome

AF:

0.996

Gnomad4 AMR exome

AF:

0.995

Gnomad4 ASJ exome

AF:

0.988

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.974

Gnomad4 FIN exome

AF:

0.988

Gnomad4 NFE exome

AF:

0.976

Gnomad4 OTH exome

AF:

0.983

GnomAD4 genome

AF:

0.986

AC:

150146

AN:

152242

Hom.:

74047

Cov.:

AF XY:

0.987

AC XY:

73479

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.996

Gnomad4 AMR

AF:

0.994

Gnomad4 ASJ

AF:

0.989

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.978

Gnomad4 FIN

AF:

0.989

Gnomad4 NFE

AF:

0.977

Gnomad4 OTH

AF:

0.988

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:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other: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. -

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over