dbSNP rs180882042: RYR3:c.14466-7G>A (chr15-33864131-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_001036.6(RYR3):c.14466-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000046 in 1,608,416 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

RYR3
NM_001036.6 splice_region, intron

Scores

Splicing: ADA: 0.0001894

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.53

Publications

0 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 links:

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]

AVEN links:

ENSG00000259287 (HGNC:58469):

ENSG00000259287 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 15-33864131-G-A is Benign according to our data. Variant chr15-33864131-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 718116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.14466-7G>A		splice_region intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.14451-7G>A		splice_region intron	N/A	NP_001230925.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RYR3	ENST00000634891.2	TSL:1 MANE Select	c.14466-7G>A	splice_region intron	N/A	ENSP00000489262.1
RYR3	ENST00000389232.9	TSL:5	c.14463-7G>A	splice_region intron	N/A	ENSP00000373884.5
RYR3	ENST00000415757.7	TSL:2	c.14451-7G>A	splice_region intron	N/A	ENSP00000399610.3

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000572

AC:

AN:

244854

AF XY:

0.0000603

show subpopulations

Gnomad AFR exome

AF:

0.000460

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000451

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000412

AC:

AN:

1456200

Hom.:

Cov.:

AF XY:

0.0000428

AC XY:

AN XY:

724262

show subpopulations

African (AFR)

AF:

0.000509

AC:

AN:

33398

American (AMR)

AF:

0.0000451

AC:

AN:

44374

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.000101

AC:

AN:

39640

South Asian (SAS)

AF:

0.000117

AC:

AN:

85502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

1108060

Other (OTH)

AF:

0.0000830

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41544

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000869

ClinVar

ClinVar submissions as Germline

Significance:Likely 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

-0.36

CADD

Benign

1.1

(source)

DANN

Benign

0.77

PhyloP100

-1.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.0040

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