rs376800501

chr19-38516056-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000540.3(RYR1):c.9555-31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,541,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.726

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-38516056-C-T is Benign according to our data. Variant chr19-38516056-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256584.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.9555-31C>T		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.9555-31C>T		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.9555-31C>T		intron_variant		1		P4
RYR1	ENST00000594335.5	c.*298-31C>T		intron_variant, NMD_transcript_variant		1
RYR1	ENST00000599547.6	c.*314-31C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000357 AC: 54 AN: 151304 Hom.: 0 AF XY: 0.000311 AC XY: 25 AN XY: 80358

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000443

Gnomad FIN exome AF: 0.0000659

Gnomad NFE exome AF: 0.000876

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.000544 AC: 756 AN: 1388914 Hom.: 0 Cov.: 31 AF XY: 0.000527 AC XY: 360 AN XY: 683364

Gnomad4 AFR exome AF: 0.0000637

Gnomad4 AMR exome AF: 0.0000563

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000380

Gnomad4 FIN exome AF: 0.0000621

Gnomad4 NFE exome AF: 0.000684

Gnomad4 OTH exome AF: 0.000192

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74496

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.000321

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	-0.81
Cadd	Benign	3.0
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376800501; hg19: chr19-39006696;