rs755502084

Positions:

• chr19-38502739-C-A
• chr19-38502739-C-G
• chr19-38502739-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000540.3(RYR1):​c.7835+12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000861 in 1,278,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.93

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-38502739-C-A is Benign according to our data. Variant chr19-38502739-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 513722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7835+12C>A		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7835+12C>A		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.7835+12C>A		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.1287+12C>A		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.7835+12C>A		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000861 AC: 11 AN: 1278078 Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 7 AN XY: 634952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 19

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RYR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.29
DANN	Benign	0.52

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

Other links and lift over

dbSNP: rs755502084; hg19: chr19-38993379;