rs2304149

Positions:

• chr19-38463400-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000540.3(RYR1):​c.2578-23C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,609,202 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0017 (8 hom., cov: 30)
  • Exomes 𝑓: 0.0017 (63 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.44

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: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-38463400-C-G is Benign according to our data. Variant chr19-38463400-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 133118.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-38463400-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00168 (255/152162) while in subpopulation EAS AF= 0.0401 (207/5162). AF 95% confidence interval is 0.0356. There are 8 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.2578-23C>G		intron_variant		ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.2578-23C>G		intron_variant		5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.2578-23C>G		intron_variant		1		P4
RYR1	ENST00000599547.6	c.2578-23C>G		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152044 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00282 AC: 699 AN: 247504 Hom.: 11 AF XY: 0.00267 AC XY: 357 AN XY: 133938

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.0309

Gnomad SAS exome AF: 0.00259

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000536

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00169 AC: 2468 AN: 1457040 Hom.: 63 Cov.: 32 AF XY: 0.00172 AC XY: 1247 AN XY: 724882

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00238

Gnomad4 EAS exome AF: 0.0505

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000523

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00168 AC: 255 AN: 152162 Hom.: 8 Cov.: 30 AF XY: 0.00198 AC XY: 147 AN XY: 74398

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0401

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000969 Hom.: 1

Bravo AF: 0.00145

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.61
BranchPoint Hunter		3.0

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: rs2304149; hg19: chr19-38954040;