rs7258075

chr19-38468556-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000540.3(RYR1):c.3382-410T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,230 control chromosomes in the GnomAD database, including 1,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: 𝑓 0.11 (1074 hom., cov: 32)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.45

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.3382-410T>G		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.3382-410T>G		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.3382-410T>G		intron_variant		1		P4
RYR1	ENST00000599547.6	c.3382-410T>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17037 AN: 152112 Hom.: 1076 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.0523

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.115

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

GnomAD4 genome AF: 0.112 AC: 17049 AN: 152230 Hom.: 1074 Cov.: 32 AF XY: 0.110 AC XY: 8221 AN XY: 74450

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0880

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.0523

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.116

Alfa AF: 0.115 Hom.: 1455

Bravo AF: 0.113

Asia WGS AF: 0.109 AC: 379 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.69
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.98

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: rs7258075; hg19: chr19-38959196;