rs2228068

Positions:

• chr19-38490644-A-C
• chr19-38490644-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000540.3(RYR1):​c.6039A>C​(p.Lys2013Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2013Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.832

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.6039A>C	p.Lys2013Asn	missense_variant	37/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6039A>C	p.Lys2013Asn	missense_variant	37/106	5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.6039A>C	p.Lys2013Asn	missense_variant	37/105	1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.6039A>C	p.Lys2013Asn	missense_variant, NMD_transcript_variant	37/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	.;D
Eigen	Benign	0.12
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.55	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.73	N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;D
Polyphen		0.94	P;P
Vest4		0.45
MutPred		0.31		Loss of methylation at K2013 (P = 0.0042);Loss of methylation at K2013 (P = 0.0042);
MVP		0.92
MPC		0.66
ClinPred		0.93	D
GERP RS		4.2
Varity_R		0.34
gMVP		0.59

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: rs2228068; hg19: chr19-38981284;