19-38483516-G-C

Variant names:

• chr19-38483516-G-C
• NM_000540.3:c.4934G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_000540.3(RYR1):​c.4934G>C​(p.Arg1645Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. R1645Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.91

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38483516-G-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the RYR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 94 curated benign missense variants. Gene score misZ: 1.918 (below the threshold of 3.09). Trascript score misZ: 3.9788 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.4934G>C	p.Arg1645Pro	missense_variant, splice_region_variant	Exon 33 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.4934G>C	p.Arg1645Pro	missense_variant, splice_region_variant	Exon 33 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.4934G>C	p.Arg1645Pro	missense_variant, splice_region_variant	Exon 33 of 105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.4934G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 33 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1392764 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 687724

Gnomad4 AFR exome AF: 0.0000312

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: 0.00

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.45		Gain of catalytic residue at R1645 (P = 0.021);Gain of catalytic residue at R1645 (P = 0.021);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-38974156;