rs3745851

chr19-38499270-C-T

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.7027+27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 1,613,978 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (202 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -2.45

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=-0.91).
• BP6: Variant 19-38499270-C-T is Benign according to our data. Variant chr19-38499270-C-T is described in ClinVar as [Benign]. Clinvar id is 133176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38499270-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7027+27C>T		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7027+27C>T		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7027+27C>T		intron_variant		1		P4
RYR1	ENST00000594335.5	c.479+27C>T		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.7027+27C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1285 AN: 152120 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0691

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0138 AC: 3473 AN: 251142 Hom.: 97 AF XY: 0.0125 AC XY: 1694 AN XY: 135796

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0603

Gnomad SAS exome AF: 0.0215

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00511 AC: 7468 AN: 1461740 Hom.: 202 Cov.: 32 AF XY: 0.00541 AC XY: 3936 AN XY: 727180

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.0412

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0733

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.00757

GnomAD4 genome AF: 0.00844 AC: 1285 AN: 152238 Hom.: 33 Cov.: 32 AF XY: 0.00999 AC XY: 744 AN XY: 74448

Gnomad4 AFR AF: 0.00429

Gnomad4 AMR AF: 0.0371

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0691

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00334 Hom.: 1

Bravo AF: 0.0109

Asia WGS AF: 0.0550 AC: 190 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2018	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.14
Dann	Benign	0.77

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: rs3745851; hg19: chr19-38989910; COSMIC: COSV62088005;