chr15-33771968-A-C

Variant names:

• chr15-33771968-A-C
• rs1555450889
• NM_001036.6:c.8865A>C
• RYR3 p.Ala2955Ala

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP6_ModerateBP7

The NM_001036.6(RYR3):c.8865A>C (p.Ala2955Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.22
• Publications: 0 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: ClinGen, G2P, PanelApp Australia
• congenital myopathy

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RYR3 NM_001036.6	MANE Select	c.8865A>C p.Ala2955Ala	synonymous	Exon 63 of 104	Prot: NP_001027.3
	RYR3 NM_001243996.4		c.8865A>C p.Ala2955Ala	synonymous	Exon 63 of 103	Prot: NP_001230925.1 UniProt:

RYR3 NM_001036.6

MANE Select

HGVSc / HGVSpc.8865A>Cp.Ala2955Ala

Exon rankExon 63 of 104

synonymous

Prot: NP_001027.3

RYR3 NM_001243996.4

HGVSc / HGVSpc.8865A>Cp.Ala2955Ala

Exon rankExon 63 of 103

synonymous

Prot: NP_001230925.1UniProt: Q15413-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RYR3 ENST00000634891.2	TSL:1MANE Select	c.8865A>C p.Ala2955Ala	synonymous	Exon 63 of 104	Prot: ENSP00000489262.1 UniProt:
	RYR3 ENST00000389232.9	TSL:5	c.8862A>C p.Ala2954Ala	synonymous	Exon 63 of 104	Prot: ENSP00000373884.5 UniProt:
	RYR3 ENST00000415757.7	TSL:2	c.8865A>C p.Ala2955Ala	synonymous	Exon 63 of 103	Prot: ENSP00000399610.3 UniProt:

RYR3 ENST00000634891.2

TSL:1MANE Select

HGVSc / HGVSpc.8865A>Cp.Ala2955Ala

Exon rankExon 63 of 104

synonymous

Prot: ENSP00000489262.1UniProt: Q15413-1

RYR3 ENST00000389232.9

TSL:5

HGVSc / HGVSpc.8862A>Cp.Ala2954Ala

Exon rankExon 63 of 104

synonymous

Prot: ENSP00000373884.5UniProt: A0A0X1KG73

RYR3 ENST00000415757.7

TSL:2

HGVSc / HGVSpc.8865A>Cp.Ala2955Ala

Exon rankExon 63 of 103

synonymous

Prot: ENSP00000399610.3UniProt: Q15413-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	48446	0.0000134	1	74554

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.0038
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.23
DANN	Benign	0.51
GPN-Star LLR	N/A	-2.2
GPN-Star score	N/A	2.2
PhyloP100	Benign	-3.2

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555450889;

hg19: chr15-34064169;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar