rs193922821

Positions:

• chr19-38502540-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_000540.3(RYR1):​c.7648C>G​(p.Leu2550Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (no stars).

• Frequency: Genomes: not found (cov: 29)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 1.55

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.
• BP6: Variant 19-38502540-C-G is Benign according to our data. Variant chr19-38502540-C-G is described in ClinVar as [Benign]. Clinvar id is 133210.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-38502540-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7648C>G	p.Leu2550Val	missense_variant	48/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7648C>G	p.Leu2550Val	missense_variant	48/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.7648C>G	p.Leu2550Val	missense_variant	48/105	1		ENSP00000347667	P4
RYR1	ENST00000594335.5	c.1102C>G	p.Leu368Val	missense_variant, NMD_transcript_variant	9/49	1		ENSP00000470927
RYR1	ENST00000599547.6	c.7648C>G	p.Leu2550Val	missense_variant, NMD_transcript_variant	48/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 29

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Central core myopathy Benign:1

Benign, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Uncertain	0.62	.;D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.80	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D;D
Polyphen		0.89	P;P
Vest4		0.64
MutPred		0.12		Loss of stability (P = 0.1773);Loss of stability (P = 0.1773);
MVP		0.92
MPC		0.34
ClinPred		0.92	D
GERP RS		3.1
Varity_R		0.37
gMVP		0.54

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: rs193922821; hg19: chr19-38993180;