rs376084861

chr15-33739929-C-Gchr15-33739929-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001036.6(RYR3):c.7754C>G(p.Thr2585Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,613,774 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2585T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00044 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00060 (8 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.95

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008882254).
• BP6: Variant 15-33739929-C-G is Benign according to our data. Variant chr15-33739929-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 531121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.7754C>G	p.Thr2585Arg	missense_variant	51/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.7754C>G	p.Thr2585Arg	missense_variant	51/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152136 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00115 AC: 287 AN: 249008 Hom.: 2 AF XY: 0.00162 AC XY: 219 AN XY: 135090

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00914

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000598 AC: 874 AN: 1461522 Hom.: 8 Cov.: 31 AF XY: 0.000857 AC XY: 623 AN XY: 727018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00950

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152252 Hom.: 1 Cov.: 31 AF XY: 0.000645 AC XY: 48 AN XY: 74434

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

RYR3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.;.;.
Eigen	Benign	-0.059
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0089	T;T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.2	L;L;.;.;.
MutationTaster	Benign	0.63	D;D
PrimateAI	Uncertain	0.59	T
Polyphen		0.071	B;P;.;.;.
Vest4		0.61
MutPred		0.36		Loss of ubiquitination at K2588 (P = 0.0666);Loss of ubiquitination at K2588 (P = 0.0666);.;Loss of ubiquitination at K2588 (P = 0.0666);.;
MVP		0.87
MPC		0.21
ClinPred		0.058	T
GERP RS		3.7
Varity_R		0.065
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs376084861; hg19: chr15-34032130;