rs202181075

chr15-33835049-A-Cchr15-33835049-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.11545A>C(p.Asn3849His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,613,708 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.25

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=0.010128081).
• BP6: Variant 15-33835049-A-C is Benign according to our data. Variant chr15-33835049-A-C is described in ClinVar as [Benign]. Clinvar id is 461844.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.11545A>C	p.Asn3849His	missense_variant	87/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.11545A>C	p.Asn3849His	missense_variant	87/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 345 AN: 152150 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00265 AC: 661 AN: 249096 Hom.: 2 AF XY: 0.00257 AC XY: 347 AN XY: 135144

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00193 AC: 2818 AN: 1461440 Hom.: 9 Cov.: 30 AF XY: 0.00185 AC XY: 1345 AN XY: 727006

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0150

Gnomad4 NFE exome AF: 0.00170

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00227 AC: 345 AN: 152268 Hom.: 1 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74454

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.000960

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000486 AC: 2

ESP6500EA AF: 0.00190 AC: 16

ExAC AF: 0.00275 AC: 333

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 12, 2023

- -

RYR3-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.25	T;.;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T;T;T;T
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	-0.73	N;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
Polyphen		0.17	B;D;.;.;.
Vest4		0.48
MVP		0.72
MPC		0.23
ClinPred		0.044	T
GERP RS		4.9
Varity_R		0.16
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202181075; hg19: chr15-34127250;