rs2304386

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001036.6(RYR3):c.280-7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,607,916 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 44 hom. )

Consequence

RYR3
NM_001036.6 splice_region, intron

Scores

Splicing: ADA: 0.002234

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.889

Publications

3 publications found

Variant links:

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

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 15-33530585-C-G is Benign according to our data. Variant chr15-33530585-C-G is described in ClinVar as Benign. ClinVar VariationId is 461898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00195 (297/152222) while in subpopulation EAS AF = 0.0425 (220/5172). AF 95% confidence interval is 0.0379. There are 10 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 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.280-7C>G		splice_region intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.280-7C>G		splice_region intron	N/A	NP_001230925.1	Q15413-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RYR3	ENST00000634891.2	TSL:1 MANE Select	c.280-7C>G	splice_region intron	N/A	ENSP00000489262.1	Q15413-1
RYR3	ENST00000389232.9	TSL:5	c.280-7C>G	splice_region intron	N/A	ENSP00000373884.5	A0A0X1KG73
RYR3	ENST00000415757.7	TSL:2	c.280-7C>G	splice_region intron	N/A	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0422

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00391

AC:

971

AN:

248312

AF XY:

0.00361

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0490

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000249

Gnomad OTH exome

AF:

0.00266

GnomAD4 exome

AF:

0.00152

AC:

2213

AN:

1455694

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1124

AN XY:

724564

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33352

American (AMR)

AF:

0.000537

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.0441

AC:

1750

AN:

39640

South Asian (SAS)

AF:

0.000860

AC:

AN:

86074

European-Finnish (FIN)

AF:

0.0000939

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000142

AC:

157

AN:

1106644

Other (OTH)

AF:

0.00327

AC:

197

AN:

60168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

107

214

322

429

536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00195

AC:

297

AN:

152222

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41542

American (AMR)

AF:

0.00203

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0425

AC:

220

AN:

5172

South Asian (SAS)

AF:

0.00125

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68016

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.00240

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epileptic encephalopathy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

8.3

(source)

DANN

Benign

0.57

PhyloP100

0.89

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0022

dbscSNV1_RF

Benign

0.10

Splicevardb

2.0

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over