rs2945049

Variant names:

• chr19-38528457-G-A
• rs2945049
• NM_000540.3:c.10937+39G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.10937+39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,606,880 control chromosomes in the GnomAD database, including 404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (229 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (175 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.376

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]

ENSG00000269445 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-38528457-G-A is Benign according to our data. Variant chr19-38528457-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38528457-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.10937+39G>A		intron_variant	Intron 74 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.10937+39G>A		intron_variant	Intron 74 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4524 AN: 152112 Hom.: 229 Cov.: 31

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00871 AC: 2185 AN: 250768 Hom.: 98 AF XY: 0.00648 AC XY: 879 AN XY: 135612

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00727

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000627

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00348 AC: 5060 AN: 1454650 Hom.: 175 Cov.: 29 AF XY: 0.00308 AC XY: 2227 AN XY: 724158

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00772

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000402

Gnomad4 OTH exome AF: 0.00802

GnomAD4 genome AF: 0.0298 AC: 4529 AN: 152230 Hom.: 229 Cov.: 31 AF XY: 0.0292 AC XY: 2172 AN XY: 74418

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0178 Hom.: 19

Bravo AF: 0.0330

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 19, 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. -

not specified Benign:1

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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	-0.83
CADD	Benign	3.6
DANN	Benign	0.45

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: rs2945049; hg19: chr19-39019097;