rs376873625

Positions:

• chr19-38463373-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000540.3(RYR1):​c.2578-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,509,220 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0220

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-38463373-G-A is Benign according to our data. Variant chr19-38463373-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256478.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.2578-50G>A		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.2578-50G>A		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.2578-50G>A		intron_variant		1		P4
RYR1	ENST00000599547.6	c.2578-50G>A		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 130 AN: 152114 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000710 AC: 162 AN: 228096 Hom.: 1 AF XY: 0.000768 AC XY: 95 AN XY: 123664

Gnomad AFR exome AF: 0.000215

Gnomad AMR exome AF: 0.000371

Gnomad ASJ exome AF: 0.000419

Gnomad EAS exome AF: 0.000702

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000363

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000881

GnomAD4 exome AF: 0.00116 AC: 1573 AN: 1357106 Hom.: 3 Cov.: 20 AF XY: 0.00110 AC XY: 745 AN XY: 679384

Gnomad4 AFR exome AF: 0.000415

Gnomad4 AMR exome AF: 0.000327

Gnomad4 ASJ exome AF: 0.000794

Gnomad4 EAS exome AF: 0.000386

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000271

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.000667

GnomAD4 genome AF: 0.000855 AC: 130 AN: 152114 Hom.: 0 Cov.: 30 AF XY: 0.000821 AC XY: 61 AN XY: 74300

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000726 Hom.: 1

Bravo AF: 0.000824

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.1
DANN	Benign	0.69

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: rs376873625; hg19: chr19-38954013;