rs966978611

chr19-38519348-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000540.3(RYR1):c.10153G>T(p.Ala3385Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3385V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16

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 1 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=0.09215692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.10153G>T	p.Ala3385Ser	missense_variant	67/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.10153G>T	p.Ala3385Ser	missense_variant	67/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.10153G>T	p.Ala3385Ser	missense_variant	67/105	1		P4
RYR1	ENST00000594335.5	c.*896G>T		3_prime_UTR_variant, NMD_transcript_variant	27/49	1
RYR1	ENST00000599547.6	c.*912G>T		3_prime_UTR_variant, NMD_transcript_variant	66/80	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460286 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726400

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Benign	0.97
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.69	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.23
Sift	Benign	0.58	T;T
Polyphen		0.0070	B;B
Vest4		0.19
MutPred		0.16		Gain of phosphorylation at A3385 (P = 0.021);Gain of phosphorylation at A3385 (P = 0.021);
MVP		0.86
MPC		0.29
ClinPred		0.21	T
GERP RS		3.5
Varity_R		0.049
gMVP		0.094

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: rs966978611; hg19: chr19-39009988;