rs114134909

chr19-38584907-G-Achr19-38584907-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):c.14647-36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,612,612 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (54 hom., cov: 29)
  • Exomes 𝑓: 0.0015 (51 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.04

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=-0.9).
• BP6: Variant 19-38584907-G-A is Benign according to our data. Variant chr19-38584907-G-A is described in ClinVar as [Benign]. Clinvar id is 256450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0145 (2207/151964) while in subpopulation AFR AF= 0.051 (2112/41404). AF 95% confidence interval is 0.0492. There are 54 homozygotes in gnomad4. There are 992 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 53 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.14647-36G>A		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.14647-36G>A		intron_variant		5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2204 AN: 151846 Hom.: 53 Cov.: 29

Gnomad AFR AF: 0.0511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00385 AC: 961 AN: 249754 Hom.: 16 AF XY: 0.00299 AC XY: 405 AN XY: 135248

Gnomad AFR exome AF: 0.0510

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.000559

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00149 AC: 2179 AN: 1460648 Hom.: 51 Cov.: 31 AF XY: 0.00131 AC XY: 955 AN XY: 726586

Gnomad4 AFR exome AF: 0.0513

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000429

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.0000846

Gnomad4 OTH exome AF: 0.00310

GnomAD4 genome AF: 0.0145 AC: 2207 AN: 151964 Hom.: 54 Cov.: 29 AF XY: 0.0134 AC XY: 992 AN XY: 74284

Gnomad4 AFR AF: 0.0510

Gnomad4 AMR AF: 0.00420

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00824 Hom.: 4

Bravo AF: 0.0166

Asia WGS AF: 0.00144 AC: 5 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 30, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.79
Dann	Benign	0.64

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: rs114134909; hg19: chr19-39075547;