rs114935281

chr19-38482993-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):c.4621-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,583,364 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (18 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (19 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08

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 19-38482993-C-T is Benign according to our data. Variant chr19-38482993-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00818 (1245/152216) while in subpopulation AFR AF= 0.0258 (1073/41526). AF 95% confidence interval is 0.0246. There are 18 homozygotes in gnomad4. There are 570 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.4621-34C>T		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.4621-34C>T		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.4621-34C>T		intron_variant		1		P4
RYR1	ENST00000599547.6	c.4621-34C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00819 AC: 1245 AN: 152098 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00308 AC: 774 AN: 251006 Hom.: 6 AF XY: 0.00248 AC XY: 336 AN XY: 135692

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000812

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00151 AC: 2164 AN: 1431148 Hom.: 19 Cov.: 28 AF XY: 0.00145 AC XY: 1033 AN XY: 713870

Gnomad4 AFR exome AF: 0.0269

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000501

Gnomad4 OTH exome AF: 0.00375

GnomAD4 genome AF: 0.00818 AC: 1245 AN: 152216 Hom.: 18 Cov.: 31 AF XY: 0.00766 AC XY: 570 AN XY: 74414

Gnomad4 AFR AF: 0.0258

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00402 Hom.: 1

Bravo AF: 0.00928

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 2013

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.9
Dann	Benign	0.66

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: rs114935281; hg19: chr19-38973633;