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15-33473445-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_001036.6(RYR3):c.78C>A(p.Ile26=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,613,856 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. I26I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00088 ( 13 hom. )

Consequence

RYR3
NM_001036.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.154
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.2).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 15-33473445-C-A is Benign according to our data. Variant chr15-33473445-C-A is described in ClinVar as [Benign]. Clinvar id is 461962.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.154 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR3NM_001036.6 linkuse as main transcriptc.78C>A p.Ile26= synonymous_variant 2/104 ENST00000634891.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR3ENST00000634891.2 linkuse as main transcriptc.78C>A p.Ile26= synonymous_variant 2/1041 NM_001036.6 P4Q15413-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000730
AC:
111
AN:
152116
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000266
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000578
Gnomad SAS
AF:
0.0155
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00174
AC:
434
AN:
249248
Hom.:
6
AF XY:
0.00226
AC XY:
305
AN XY:
135222
show subpopulations
Gnomad AFR exome
AF:
0.000129
Gnomad AMR exome
AF:
0.000377
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00106
Gnomad SAS exome
AF:
0.0124
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000885
Gnomad OTH exome
AF:
0.00182
GnomAD4 exome
AF:
0.000885
AC:
1293
AN:
1461622
Hom.:
13
Cov.:
32
AF XY:
0.00124
AC XY:
902
AN XY:
727108
show subpopulations
Gnomad4 AFR exome
AF:
0.000358
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000831
Gnomad4 SAS exome
AF:
0.0120
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000101
Gnomad4 OTH exome
AF:
0.00124
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000742
AC:
113
AN:
152234
Hom.:
0
Cov.:
32
AF XY:
0.000927
AC XY:
69
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000580
Gnomad4 SAS
AF:
0.0160
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000156
Hom.:
0
Bravo
AF:
0.000321
Asia WGS
AF:
0.0110
AC:
39
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000296

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Epileptic encephalopathy Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeSep 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.20
Cadd
Benign
0.41
Dann
Benign
0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199968653; hg19: chr15-33765646; API