rs193922847

chr19-38561165-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000540.3(RYR1):c.12335C>T(p.Ser4112Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S4112S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 7.84

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.12335C>T	p.Ser4112Leu	missense_variant	90/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.12335C>T	p.Ser4112Leu	missense_variant	90/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249292 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134984

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 19, 2018	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.78		.;Gain of catalytic residue at S4112 (P = 0.0126);
MVP		0.98
MPC		0.51
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.76
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs193922847; hg19: chr19-39051805; COSMIC: COSV62087989;