chr15-33530585-C-G

Variant names:

• chr15-33530585-C-G
• rs2304386
• NM_001036.6:c.280-7C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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

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

ACMG classification

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

Selected	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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152104 Hom.: 10 Cov.: 32

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

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.: 44 Cov.: 29 AF XY: 0.00155 AC XY: 1124 AN XY: 724564

African (AFR) AF: 0.0000899 AC: 3 AN: 33352

American (AMR) AF: 0.000537 AC: 24 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0441 AC: 1750 AN: 39640

South Asian (SAS) AF: 0.000860 AC: 74 AN: 86074

European-Finnish (FIN) AF: 0.0000939 AC: 5 AN: 53266

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.000142 AC: 157 AN: 1106644

Other (OTH) AF: 0.00327 AC: 197 AN: 60168

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152222 Hom.: 10 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74436

African (AFR) AF: 0.000217 AC: 9 AN: 41542

American (AMR) AF: 0.00203 AC: 31 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0425 AC: 220 AN: 5172

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.00240

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.3
DANN	Benign	0.57
PhyloP100		0.89
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304386; hg19: chr15-33822786; COSMIC: COSV66791978; COSMIC: COSV66791978;