rs193922845

chr19-38548379-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000540.3(RYR1):c.12241A>T(p.Thr4081Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T4081M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.76

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 where missense usually causes diseases, RYR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.28930852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.12241A>T	p.Thr4081Ser	missense_variant	89/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.12241A>T	p.Thr4081Ser	missense_variant	89/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	18
Dann	Benign	0.85
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	0.89	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.26
Sift	Benign	0.29	T;T
Polyphen		0.79	P;P
Vest4		0.46
MutPred		0.35		.;Gain of disorder (P = 0.0265);
MVP		0.93
MPC		0.51
ClinPred		0.66	D
GERP RS		4.4
Varity_R		0.097
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: rs193922845; hg19: chr19-39039019;