19-38566953-G-C

Position:

• chr19-38566953-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000540.3(RYR1):​c.13480G>C​(p.Glu4494Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. 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. E4494K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.98

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.13480G>C	p.Glu4494Gln	missense_variant	92/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.13480G>C	p.Glu4494Gln	missense_variant	92/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453916 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 722424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	0.0028	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	12
DANN	Benign	0.71
DEOGEN2	Uncertain	0.61	.;D
Eigen	Benign	0.093
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.63	T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.5	.;M
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.99	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.13	T;T
Polyphen		0.90	P;P
Vest4		0.11
MutPred		0.39		.;Loss of solvent accessibility (P = 0.0174);
MVP		0.97
MPC		0.57
ClinPred		0.57	D
GERP RS		3.8
Varity_R		0.093
gMVP		0.46

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: rs143849895; hg19: chr19-39057593;