rs182257230

Variant names:

• chr15-33857882-G-A
• rs182257230
• NM_001036.6:c.14110G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001036.6(RYR3):​c.14110G>A​(p.Glu4704Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00901 in 1,614,098 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (74 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 8.00
• Publications: 9 publications found

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]

AVEN (HGNC:13509): (apoptosis and caspase activation inhibitor) Involved in negative regulation of apoptotic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009003162).
• BP6: Variant 15-33857882-G-A is Benign according to our data. Variant chr15-33857882-G-A is described in ClinVar as Benign. ClinVar VariationId is 461872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.14110G>A	p.Glu4704Lys	missense	Exon 99 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.14095G>A	p.Glu4699Lys	missense	Exon 98 of 103	NP_001230925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.14110G>A	p.Glu4704Lys	missense	Exon 99 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.14107G>A	p.Glu4703Lys	missense	Exon 99 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.14095G>A	p.Glu4699Lys	missense	Exon 98 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1082 AN: 152112 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00762 AC: 1904 AN: 249830 AF XY: 0.00782

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00774

GnomAD4 exome AF: 0.00921 AC: 13467 AN: 1461866 Hom.: 74 Cov.: 30 AF XY: 0.00913 AC XY: 6643 AN XY: 727230

African (AFR) AF: 0.00128 AC: 43 AN: 33480

American (AMR) AF: 0.00331 AC: 148 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00604 AC: 521 AN: 86258

European-Finnish (FIN) AF: 0.0151 AC: 805 AN: 53410

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11417 AN: 1111994

Other (OTH) AF: 0.00818 AC: 494 AN: 60396

GnomAD4 genome AF: 0.00711 AC: 1082 AN: 152232 Hom.: 5 Cov.: 32 AF XY: 0.00709 AC XY: 528 AN XY: 74426

African (AFR) AF: 0.00169 AC: 70 AN: 41500

American (AMR) AF: 0.00549 AC: 84 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4822

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 747 AN: 68036

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.00854 Hom.: 27

Bravo AF: 0.00609

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00841 AC: 1020

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00960

EpiControl AF: 0.00800

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Epileptic encephalopathy (1)
-	-	1	RYR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0090	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.54
Sift	Benign	0.053	T
Sift4G	Benign	0.088	T
Polyphen		0.52	P
Vest4		0.61
MVP		0.73
MPC		0.91
ClinPred		0.018	T
GERP RS		4.8
Varity_R		0.27
gMVP		0.88
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs182257230; hg19: chr15-34150083; COSMIC: COSV66793882; COSMIC: COSV66793882;