rs146838868

Variant names:

• chr15-33579984-A-G
• rs146838868
• NM_001036.6:c.1277A>G

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.1277A>G​(p.Asn426Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,608,642 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (19 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.77
• Publications: 8 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]

RYR3 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: G2P, PanelApp Australia, ClinGen
• congenital myopathy

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069306195).
• BP6: Variant 15-33579984-A-G is Benign according to our data. Variant chr15-33579984-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.1277A>G	p.Asn426Ser	missense	Exon 13 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.1277A>G	p.Asn426Ser	missense	Exon 13 of 103	NP_001230925.1	Q15413-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.1277A>G	p.Asn426Ser	missense	Exon 13 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.1277A>G	p.Asn426Ser	missense	Exon 13 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.1277A>G	p.Asn426Ser	missense	Exon 13 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 151978 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00698

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0268

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00281 AC: 687 AN: 244072 AF XY: 0.00279

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00694

Gnomad FIN exome AF: 0.0214

Gnomad NFE exome AF: 0.000802

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.00127 AC: 1852 AN: 1456546 Hom.: 19 Cov.: 32 AF XY: 0.00125 AC XY: 902 AN XY: 724252

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.0000455 AC: 2 AN: 43910

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25846

East Asian (EAS) AF: 0.0118 AC: 465 AN: 39552

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85370

European-Finnish (FIN) AF: 0.0190 AC: 1011 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.000265 AC: 294 AN: 1109482

Other (OTH) AF: 0.00116 AC: 70 AN: 60106

GnomAD4 genome AF: 0.00250 AC: 380 AN: 152096 Hom.: 4 Cov.: 32 AF XY: 0.00371 AC XY: 276 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41506

American (AMR) AF: 0.000196 AC: 3 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00699 AC: 36 AN: 5148

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.0268 AC: 284 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 67986

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000423

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000477 AC: 4

ExAC AF: 0.00244 AC: 295

Asia WGS AF: 0.00289 AC: 10 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.085
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0069	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.20	T
Polyphen		0.026	B
Vest4		0.093
MVP		0.78
MPC		0.14
ClinPred		0.042	T
GERP RS		2.9
Varity_R		0.064
gMVP		0.12
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146838868; hg19: chr15-33872185;