rs776194441

chr19-38483429-C-Achr19-38483429-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000540.3(RYR1):c.4847C>A(p.Thr1616Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,424,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T1616M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.812

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.4847C>A	p.Thr1616Lys	missense_variant	33/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.4847C>A	p.Thr1616Lys	missense_variant	33/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.4847C>A	p.Thr1616Lys	missense_variant	33/105	1		P4
RYR1	ENST00000599547.6	c.4847C>A	p.Thr1616Lys	missense_variant, NMD_transcript_variant	33/80	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1424418 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 705218

Gnomad4 AFR exome AF: 0.0000607

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	0.11
Eigen_PC	Benign	-0.0082
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.87	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.012	D;D
Polyphen		0.99	D;D
Vest4		0.67
MutPred		0.34		Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);
MVP		0.99
MPC		0.92
ClinPred		0.79	D
GERP RS		4.0
Varity_R		0.29
gMVP		0.74

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: rs776194441; hg19: chr19-38974069;