rs2229119

chr15-33629953-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001036.6(RYR3):c.2693A>G(p.Asn898Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0016 in 1,599,656 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.08

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01195538).
• BP6: Variant 15-33629953-A-G is Benign according to our data. Variant chr15-33629953-A-G is described in ClinVar as [Benign]. Clinvar id is 461896.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.2693A>G	p.Asn898Ser	missense_variant	22/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.2693A>G	p.Asn898Ser	missense_variant	22/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 223 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00154 AC: 359 AN: 233406 Hom.: 0 AF XY: 0.00149 AC XY: 187 AN XY: 125700

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.000860

Gnomad ASJ exome AF: 0.000724

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00790

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000865

GnomAD4 exome AF: 0.00162 AC: 2342 AN: 1447292 Hom.: 3 Cov.: 28 AF XY: 0.00161 AC XY: 1158 AN XY: 718868

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.000891

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00722

Gnomad4 NFE exome AF: 0.00165

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.00169 AC XY: 126 AN XY: 74504

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00678

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.000956

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00110 AC: 9

ExAC AF: 0.00106 AC: 128

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.70	N;N;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
Polyphen		0.98	D;D;.;.;.
Vest4		0.50
MVP		0.77
MPC		0.51
ClinPred		0.035	T
GERP RS		5.3
Varity_R		0.59
gMVP		0.16

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: rs2229119; hg19: chr15-33922154;