rs193169917

Positions:

• chr19-38444130-A-G

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.425-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,604,706 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (17 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.82

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=-0.83).
• BP6: Variant 19-38444130-A-G is Benign according to our data. Variant chr19-38444130-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00269 (409/152146) while in subpopulation NFE AF= 0.00272 (185/67962). AF 95% confidence interval is 0.0024. There are 2 homozygotes in gnomad4. There are 249 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.425-19A>G		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.425-19A>G		intron_variant		5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.425-19A>G		intron_variant		1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.425-19A>G		intron_variant		2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152028 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00269 AC: 676 AN: 251284 Hom.: 5 AF XY: 0.00289 AC XY: 393 AN XY: 135836

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00160 AC: 2330 AN: 1452560 Hom.: 17 Cov.: 31 AF XY: 0.00172 AC XY: 1241 AN XY: 723312

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0181

Gnomad4 NFE exome AF: 0.00116

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00269 AC: 409 AN: 152146 Hom.: 2 Cov.: 32 AF XY: 0.00335 AC XY: 249 AN XY: 74376

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0206

Gnomad4 NFE AF: 0.00272

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00330 Hom.: 0

Bravo AF: 0.000820

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.046
DANN	Benign	0.53

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: rs193169917; hg19: chr19-38934770;