rs146201205

Positions:

• chr15-33821528-A-G

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.10921A>G​(p.Met3641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,960 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.41

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]

RYR3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006754726).
• BP6: Variant 15-33821528-A-G is Benign according to our data. Variant chr15-33821528-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 461835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6	c.10921A>G	p.Met3641Val	missense_variant	80/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.10921A>G	p.Met3641Val	missense_variant	80/104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 258 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00208 AC: 517 AN: 249122 Hom.: 3 AF XY: 0.00225 AC XY: 304 AN XY: 135142

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000927

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00966

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.00122 AC: 1784 AN: 1461664 Hom.: 6 Cov.: 32 AF XY: 0.00135 AC XY: 984 AN XY: 727122

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00263

Gnomad4 FIN exome AF: 0.00854

Gnomad4 NFE exome AF: 0.000800

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00209 AC XY: 156 AN XY: 74472

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00933

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.000763

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000829 AC: 7

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: 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	Sep 01, 2023	RYR3: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.46
DEOGEN2	Benign	0.33	T;.;.;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
MetaRNN	Benign	0.0068	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.69	N;.;.;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	.;N;.;.;.
REVEL	Benign	0.17
Sift	Benign	1.0	.;T;.;.;.
Polyphen		0.0020	B;B;.;.;.
Vest4		0.37
MVP		0.47
MPC		0.19
ClinPred		0.0075	T
GERP RS		4.2
Varity_R		0.16
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs146201205; hg19: chr15-34113729;