rs73930595

chr19-38496377-A-G

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.6664-32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,613,678 control chromosomes in the GnomAD database, including 1,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (475 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1147 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.515

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-38496377-A-G is Benign according to our data. Variant chr19-38496377-A-G is described in ClinVar as [Benign]. Clinvar id is 256539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.6664-32A>G		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.6664-32A>G		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.6664-32A>G		intron_variant		1		P4
RYR1	ENST00000594335.5	c.116-32A>G		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.6664-32A>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8822 AN: 152120 Hom.: 473 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0688

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0325 AC: 8146 AN: 250712 Hom.: 268 AF XY: 0.0298 AC XY: 4043 AN XY: 135684

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00970

Gnomad FIN exome AF: 0.0661

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0255

GnomAD4 exome AF: 0.0335 AC: 48964 AN: 1461440 Hom.: 1147 Cov.: 32 AF XY: 0.0324 AC XY: 23538 AN XY: 727020

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.0176

Gnomad4 ASJ exome AF: 0.0191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00910

Gnomad4 FIN exome AF: 0.0629

Gnomad4 NFE exome AF: 0.0331

Gnomad4 OTH exome AF: 0.0350

GnomAD4 genome AF: 0.0580 AC: 8837 AN: 152238 Hom.: 475 Cov.: 32 AF XY: 0.0583 AC XY: 4340 AN XY: 74438

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.0688

Gnomad4 NFE AF: 0.0280

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0355 Hom.: 46

Bravo AF: 0.0582

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	4.1
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs73930595; hg19: chr19-38987017;