rs181264765

chr15-33707052-A-C

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.6617A>C(p.Asn2206Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,613,910 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (21 hom.)
• Consequence: RYR3 NM_001036.6 missense, splice_region
• Scores: Splicing: ADA: 0.8759
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 9.22

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=0.034886897).
• BP6: Variant 15-33707052-A-C is Benign according to our data. Variant chr15-33707052-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 461936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-33707052-A-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/104	5		A1
RYR3	ENST00000415757.7	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/103	2		A2
RYR3	ENST00000634418.1	c.6617A>C	p.Asn2206Thr	missense_variant, splice_region_variant	43/102	5

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 235 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00226 AC: 562 AN: 249044 Hom.: 7 AF XY: 0.00246 AC XY: 333 AN XY: 135108

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000870

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00680

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00303 AC: 4430 AN: 1461582 Hom.: 21 Cov.: 31 AF XY: 0.00315 AC XY: 2288 AN XY: 727068

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00627

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00316

Gnomad4 OTH exome AF: 0.00310

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74478

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00253 Hom.: 0

Bravo AF: 0.00172

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00283 AC: 24

ExAC AF: 0.00208 AC: 252

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00267

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 15, 2023

- -

RYR3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant classified as Uncertain significance and reported on 03-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.035	T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
Polyphen		1.0	D;D;.;.;.
Vest4		0.78
MVP		0.94
MPC		0.70
ClinPred		0.021	T
GERP RS		5.3
Varity_R		0.79
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.040		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: rs181264765; hg19: chr15-33999253;