19-38457716-T-C

Variant names:

• chr19-38457716-T-C
• rs2071085
• NM_000540.3:c.1925+86T>C

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.1925+86T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,395,246 control chromosomes in the GnomAD database, including 290,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32069 hom., cov: 30)
  • Exomes 𝑓: 0.64 (258659 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.89

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=-0.92).
• BP6: Variant 19-38457716-T-C is Benign according to our data. Variant chr19-38457716-T-C is described in ClinVar as [Benign]. Clinvar id is 133110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38457716-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.1925+86T>C		intron_variant	Intron 17 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.1925+86T>C		intron_variant	Intron 17 of 105	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.1925+86T>C		intron_variant	Intron 17 of 104	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.1925+86T>C		intron_variant	Intron 17 of 79	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.646 AC: 98075 AN: 151766 Hom.: 32051 Cov.: 30

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.649

GnomAD4 exome AF: 0.641 AC: 796954 AN: 1243362 Hom.: 258659 AF XY: 0.635 AC XY: 398987 AN XY: 628798

Gnomad4 AFR exome AF: 0.603

Gnomad4 AMR exome AF: 0.692

Gnomad4 ASJ exome AF: 0.668

Gnomad4 EAS exome AF: 0.647

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.694

Gnomad4 NFE exome AF: 0.654

Gnomad4 OTH exome AF: 0.646

GnomAD4 genome AF: 0.646 AC: 98132 AN: 151884 Hom.: 32069 Cov.: 30 AF XY: 0.642 AC XY: 47662 AN XY: 74202

Gnomad4 AFR AF: 0.612

Gnomad4 AMR AF: 0.699

Gnomad4 ASJ AF: 0.672

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.420

Gnomad4 FIN AF: 0.709

Gnomad4 NFE AF: 0.661

Gnomad4 OTH AF: 0.643

Alfa AF: 0.648 Hom.: 19134

Bravo AF: 0.649

Asia WGS AF: 0.457 AC: 1591 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	12
DANN	Benign	0.47

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: rs2071085; hg19: chr19-38948356; COSMIC: COSV62092577;