rs61996340

Positions:

• chr15-33757532-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001036.6(RYR3):​c.8641T>A​(p.Ser2881Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,611,362 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (40 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.54

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058378577).
• BP6: Variant 15-33757532-T-A is Benign according to our data. Variant chr15-33757532-T-A is described in ClinVar as [Benign]. Clinvar id is 461972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1735/152216) while in subpopulation AFR AF= 0.0395 (1641/41524). AF 95% confidence interval is 0.0379. There are 24 homozygotes in gnomad4. There are 785 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6	c.8641T>A	p.Ser2881Thr	missense_variant	60/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.8641T>A	p.Ser2881Thr	missense_variant	60/104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1732 AN: 152098 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

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: 0.000118

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00277 AC: 679 AN: 244784 Hom.: 10 AF XY: 0.00202 AC XY: 268 AN XY: 132544

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000681

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00120 AC: 1751 AN: 1459146 Hom.: 40 Cov.: 31 AF XY: 0.00104 AC XY: 758 AN XY: 725386

Gnomad4 AFR exome AF: 0.0419

Gnomad4 AMR exome AF: 0.00196

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000352

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.0114 AC: 1735 AN: 152216 Hom.: 24 Cov.: 32 AF XY: 0.0105 AC XY: 785 AN XY: 74436

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.00504

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00176 Hom.: 3

Bravo AF: 0.0135

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0395 AC: 153

ESP6500EA AF: 0.000603 AC: 5

ExAC AF: 0.00351 AC: 424

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.35
DEOGEN2	Benign	0.24	T;.;.;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	D;D;D;D;D
MetaRNN	Benign	0.0058	T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	-0.23	N;N;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.010	.;N;D;.;.
REVEL	Uncertain	0.34
Sift	Benign	1.0	.;T;T;.;.
Polyphen		0.035	B;B;.;.;.
Vest4		0.35
MVP		0.44
MPC		0.17
ClinPred		0.013	T
GERP RS		5.4
Varity_R		0.070
gMVP		0.25

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: rs61996340; hg19: chr15-34049733;