rs199849275

chr19-38502851-G-GA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000540.3(RYR1):c.7836-28dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,600,600 control chromosomes in the GnomAD database, including 267 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 29)
  • Exomes 𝑓: 0.014 (253 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.62

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 -10 ACMG points.

• BP6: Variant 19-38502851-G-GA is Benign according to our data. Variant chr19-38502851-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 256561.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0109 (1653/151022) while in subpopulation NFE AF= 0.0172 (1162/67616). AF 95% confidence interval is 0.0164. There are 14 homozygotes in gnomad4. There are 751 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7836-28dup		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7836-28dup		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7836-28dup		intron_variant		1		P4
RYR1	ENST00000594335.5	c.1288-28dup		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.7836-28dup		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1653 AN: 150908 Hom.: 14 Cov.: 29

Gnomad AFR AF: 0.00312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00337

Gnomad FIN AF: 0.00803

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0111

GnomAD3 exomes AF: 0.00918 AC: 2221 AN: 241952 Hom.: 22 AF XY: 0.00950 AC XY: 1248 AN XY: 131360

Gnomad AFR exome AF: 0.00220

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.00624

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.0136 AC: 19697 AN: 1449578 Hom.: 253 Cov.: 33 AF XY: 0.0134 AC XY: 9658 AN XY: 721456

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00944

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00309

Gnomad4 FIN exome AF: 0.00876

Gnomad4 NFE exome AF: 0.0157

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0109 AC: 1653 AN: 151022 Hom.: 14 Cov.: 29 AF XY: 0.0102 AC XY: 751 AN XY: 73756

Gnomad4 AFR AF: 0.00311

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000392

Gnomad4 SAS AF: 0.00358

Gnomad4 FIN AF: 0.00803

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0110

Alfa AF: 0.00759 Hom.: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

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: rs199849275; hg19: chr19-38993491;