19-38512513-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.9472+30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,598,026 control chromosomes in the GnomAD database, including 3,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (281 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3464 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.49

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=-0.95).
• BP6: Variant 19-38512513-C-T is Benign according to our data. Variant chr19-38512513-C-T is described in ClinVar as [Benign]. Clinvar id is 256583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.9472+30C>T		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.9472+30C>T		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.9472+30C>T		intron_variant		1		P4
RYR1	ENST00000594335.5	c.*215+30C>T		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.*231+30C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8366 AN: 152176 Hom.: 281 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0579

Gnomad EAS AF: 0.00635

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0857

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0630

GnomAD3 exomes AF: 0.0671 AC: 16140 AN: 240568 Hom.: 659 AF XY: 0.0699 AC XY: 9181 AN XY: 131272

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.0711

Gnomad ASJ exome AF: 0.0478

Gnomad EAS exome AF: 0.00262

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0865

Gnomad NFE exome AF: 0.0662

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0660 AC: 95448 AN: 1445732 Hom.: 3464 Cov.: 32 AF XY: 0.0678 AC XY: 48781 AN XY: 719978

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.0677

Gnomad4 ASJ exome AF: 0.0504

Gnomad4 EAS exome AF: 0.0123

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.0812

Gnomad4 NFE exome AF: 0.0648

Gnomad4 OTH exome AF: 0.0606

GnomAD4 genome AF: 0.0550 AC: 8372 AN: 152294 Hom.: 281 Cov.: 32 AF XY: 0.0568 AC XY: 4227 AN XY: 74468

Gnomad4 AFR AF: 0.0341

Gnomad4 AMR AF: 0.0476

Gnomad4 ASJ AF: 0.0579

Gnomad4 EAS AF: 0.00637

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0857

Gnomad4 NFE AF: 0.0639

Gnomad4 OTH AF: 0.0633

Alfa AF: 0.0577 Hom.: 54

Bravo AF: 0.0501

Asia WGS AF: 0.0690 AC: 240 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 28, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.019
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77374921; hg19: chr19-39003153; COSMIC: COSV62114812;