Genetic Variant RYR3:p.Asn242Ser (chr15-33543700-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001036.6(RYR3):c.725A>G(p.Asn242Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,611,156 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 4 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.863

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: ClinGen, G2P
congenital myopathy
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059782565).

BP6

Variant 15-33543700-A-G is Benign according to our data. Variant chr15-33543700-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 531130.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.725A>G	p.Asn242Ser	missense	Exon 8 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.725A>G	p.Asn242Ser	missense	Exon 8 of 103	NP_001230925.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR3	ENST00000634891.2	TSL:1 MANE Select	c.725A>G	p.Asn242Ser	missense	Exon 8 of 104	ENSP00000489262.1
RYR3	ENST00000389232.9	TSL:5	c.725A>G	p.Asn242Ser	missense	Exon 8 of 104	ENSP00000373884.5
RYR3	ENST00000415757.7	TSL:2	c.725A>G	p.Asn242Ser	missense	Exon 8 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000976

AC:

243

AN:

248884

AF XY:

0.00124

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.000487

AC:

711

AN:

1458848

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

489

AN XY:

725930

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33396

American (AMR)

AF:

0.0000447

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39676

South Asian (SAS)

AF:

0.00666

AC:

574

AN:

86206

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000694

AC:

AN:

1109362

Other (OTH)

AF:

0.000780

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000309

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41588

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00725

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.000117

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.00110

AC:

133

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.33

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.032

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.69

MutationAssessor

Benign

-0.97

PhyloP100

0.86

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.47

REVEL

Uncertain

0.33

Sift

Benign

0.55

Polyphen

0.0010

Vest4

0.15

MutPred

0.36

Gain of disorder (P = 0.0501)

MVP

0.38

MPC

0.14

ClinPred

0.071

GERP RS

5.0

Varity_R

0.055

gMVP

0.26

Mutation Taster

=95/5

polymorphism

(source)

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

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