rs200793331

Positions:

• chr19-38504713-C-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.8068-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,569,060 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00085 (4 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.439

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=-0.87).
• BP6: Variant 19-38504713-C-T is Benign according to our data. Variant chr19-38504713-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256571.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 = 0.00498 (658/132254) while in subpopulation AFR AF= 0.0173 (557/32224). AF 95% confidence interval is 0.0161. There are 5 homozygotes in gnomad4. There are 320 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8068-35C>T		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8068-35C>T		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.8068-35C>T		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.1520-35C>T		intron_variant, NMD_transcript_variant		1		ENSP00000470927
RYR1	ENST00000599547.6	c.8068-35C>T		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 658 AN: 132226 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00200

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000276

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00389

GnomAD3 exomes AF: 0.00213 AC: 473 AN: 222508 Hom.: 1 AF XY: 0.00169 AC XY: 203 AN XY: 120450

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.0000618

Gnomad SAS exome AF: 0.0000416

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.000542

GnomAD4 exome AF: 0.000849 AC: 1220 AN: 1436806 Hom.: 4 Cov.: 33 AF XY: 0.000776 AC XY: 555 AN XY: 715586

Gnomad4 AFR exome AF: 0.0141

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000708

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00498 AC: 658 AN: 132254 Hom.: 5 Cov.: 31 AF XY: 0.00499 AC XY: 320 AN XY: 64120

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.00200

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000277

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00387

Alfa AF: 0.00446 Hom.: 2

Bravo AF: 0.00511

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.0
DANN	Benign	0.82

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: rs200793331; hg19: chr19-38995353;