rs41279214

Positions:

• chr15-33739987-C-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.7812C>G​(p.Asn2604Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,613,558 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (12 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.302

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=0.0192343).
• BP6: Variant 15-33739987-C-G is Benign according to our data. Variant chr15-33739987-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 461957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.7812C>G	p.Asn2604Lys	missense_variant	51/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.7812C>G	p.Asn2604Lys	missense_variant	51/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152166 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00211 AC: 524 AN: 248888 Hom.: 1 AF XY: 0.00201 AC XY: 272 AN XY: 135026

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00388

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00374 AC: 5467 AN: 1461274 Hom.: 12 Cov.: 32 AF XY: 0.00367 AC XY: 2666 AN XY: 726910

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00270

Gnomad4 NFE exome AF: 0.00465

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152284 Hom.: 3 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74466

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00356 Hom.: 0

Bravo AF: 0.00187

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000510 AC: 2

ESP6500EA AF: 0.00505 AC: 42

ExAC AF: 0.00198 AC: 240

EpiCase AF: 0.00349

EpiControl AF: 0.00338

ClinVar

Significance: Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 12/04/2018 by 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RYR3: BS2 -

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

RYR3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;.;.
Eigen	Benign	0.031
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D;T;D;D;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.019	T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.6	M;M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	.;D;.;.;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	.;D;.;.;.
Polyphen		0.36	B;B;.;.;.
Vest4		0.62
MutPred		0.67		Gain of ubiquitination at N2604 (P = 0.0117);Gain of ubiquitination at N2604 (P = 0.0117);.;Gain of ubiquitination at N2604 (P = 0.0117);.;
MVP		0.93
MPC		0.34
ClinPred		0.042	T
GERP RS		3.5
Varity_R		0.65
gMVP		0.39

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: rs41279214; hg19: chr15-34032188;