19-38444726-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.631+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 1,416,604 control chromosomes in the GnomAD database, including 1,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (314 hom., cov: 28)
  • Exomes 𝑓: 0.044 (1526 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0210

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=-0.83).
• BP6: Variant 19-38444726-C-T is Benign according to our data. Variant chr19-38444726-C-T is described in ClinVar as [Benign]. Clinvar id is 256532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38444726-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.631+49C>T		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.631+49C>T		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.631+49C>T		intron_variant		1		P4
RYR1	ENST00000599547.6	c.631+49C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0564 AC: 8537 AN: 151394 Hom.: 315 Cov.: 28

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0990

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0954

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.0426

Gnomad OTH AF: 0.0576

GnomAD3 exomes AF: 0.0516 AC: 10330 AN: 200180 Hom.: 363 AF XY: 0.0521 AC XY: 5630 AN XY: 108060

Gnomad AFR exome AF: 0.0857

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0964

Gnomad EAS exome AF: 0.0157

Gnomad SAS exome AF: 0.0549

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0538

GnomAD4 exome AF: 0.0438 AC: 55415 AN: 1265092 Hom.: 1526 Cov.: 18 AF XY: 0.0446 AC XY: 28342 AN XY: 635012

Gnomad4 AFR exome AF: 0.0905

Gnomad4 AMR exome AF: 0.0253

Gnomad4 ASJ exome AF: 0.0999

Gnomad4 EAS exome AF: 0.00837

Gnomad4 SAS exome AF: 0.0530

Gnomad4 FIN exome AF: 0.0926

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0490

GnomAD4 genome AF: 0.0564 AC: 8552 AN: 151512 Hom.: 314 Cov.: 28 AF XY: 0.0587 AC XY: 4345 AN XY: 73972

Gnomad4 AFR AF: 0.0808

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.0990

Gnomad4 EAS AF: 0.0148

Gnomad4 SAS AF: 0.0509

Gnomad4 FIN AF: 0.0954

Gnomad4 NFE AF: 0.0426

Gnomad4 OTH AF: 0.0570

Alfa AF: 0.0513 Hom.: 118

Bravo AF: 0.0530

Asia WGS AF: 0.0340 AC: 117 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 18, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.4
Dann	Benign	0.70

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: rs57132842; hg19: chr19-38935366;