rs199500216

Positions:

• chr15-33623935-G-A
• chr15-33623935-G-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.2486G>A​(p.Arg829His) variant causes a missense change. The variant allele was found at a frequency of 0.00132 in 1,613,902 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 5.04

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=0.020332992).
• BP6: Variant 15-33623935-G-A is Benign according to our data. Variant chr15-33623935-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 461891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6	c.2486G>A	p.Arg829His	missense_variant	20/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.2486G>A	p.Arg829His	missense_variant	20/104	1	NM_001036.6	ENSP00000489262	P4
RYR3	ENST00000389232.9	c.2486G>A	p.Arg829His	missense_variant	20/104	5		ENSP00000373884	A1
RYR3	ENST00000415757.7	c.2486G>A	p.Arg829His	missense_variant	20/103	2		ENSP00000399610	A2
RYR3	ENST00000634418.1	c.2486G>A	p.Arg829His	missense_variant	20/102	5		ENSP00000489529

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00114 AC: 284 AN: 249094 Hom.: 1 AF XY: 0.00117 AC XY: 158 AN XY: 135122

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00163

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00133 AC: 1946 AN: 1461648 Hom.: 2 Cov.: 32 AF XY: 0.00129 AC XY: 936 AN XY: 727110

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74450

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.00147

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.00133 AC: 11

ExAC AF: 0.00117 AC: 141

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00261

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	RYR3: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Flexion contracture Uncertain:1

Uncertain significance, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.;.;.
Eigen	Benign	0.095
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.020	T;T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.3	L;L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	.;N;N;.;.
REVEL	Uncertain	0.46
Sift	Benign	0.47	.;T;T;.;.
Polyphen		0.52	P;P;.;.;.
Vest4		0.36
MVP		0.86
MPC		0.79
ClinPred		0.025	T
GERP RS		3.9
Varity_R		0.078
gMVP		0.43

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: rs199500216; hg19: chr15-33916136; COSMIC: COSV66783919; COSMIC: COSV66783919;