19-38515297-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000540.3(RYR1):c.9554+190G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 152,162 control chromosomes in the GnomAD database, including 1,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (1317 hom., cov: 31)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.390

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 19-38515297-G-T is Benign according to our data. Variant chr19-38515297-G-T is described in ClinVar as [Benign]. Clinvar id is 133243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-38515297-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.9554+190G>T		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.9554+190G>T		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.9554+190G>T		intron_variant		1		P4
RYR1	ENST00000594335.5	c.*297+190G>T		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.*313+190G>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18707 AN: 152044 Hom.: 1312 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.0478

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0952

Gnomad OTH AF: 0.129

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.123 AC: 18745 AN: 152162 Hom.: 1317 Cov.: 31 AF XY: 0.124 AC XY: 9254 AN XY: 74390

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.0810

Gnomad4 EAS AF: 0.166

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.0478

Gnomad4 NFE AF: 0.0952

Gnomad4 OTH AF: 0.135

Alfa AF: 0.0927 Hom.: 545

Bravo AF: 0.125

Asia WGS AF: 0.241 AC: 836 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	1.5
Dann	Benign	0.80

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: rs2915942; hg19: chr19-39005937; COSMIC: COSV62112131;