15-33621286-A-G

Variant names:

• chr15-33621286-A-G
• rs7168848
• NM_001036.6:c.2358-2521A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001036.6(RYR3):​c.2358-2521A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,168 control chromosomes in the GnomAD database, including 2,775 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2775 hom., cov: 32)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.60
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

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.2358-2521A>G		intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.2358-2521A>G		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.2358-2521A>G		intron	N/A	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.2358-2521A>G		intron	N/A	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.2358-2521A>G		intron	N/A	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26470 AN: 152050 Hom.: 2771 Cov.: 32

Gnomad AFR AF: 0.0577

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.169

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.174 AC: 26486 AN: 152168 Hom.: 2775 Cov.: 32 AF XY: 0.179 AC XY: 13325 AN XY: 74380

African (AFR) AF: 0.0576 AC: 2393 AN: 41536

American (AMR) AF: 0.251 AC: 3833 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 499 AN: 3468

East Asian (EAS) AF: 0.164 AC: 850 AN: 5170

South Asian (SAS) AF: 0.235 AC: 1132 AN: 4816

European-Finnish (FIN) AF: 0.271 AC: 2861 AN: 10562

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14288 AN: 68012

Other (OTH) AF: 0.171 AC: 361 AN: 2112

Alfa AF: 0.199 Hom.: 5343

Bravo AF: 0.169

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.18
DANN	Benign	0.70
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7168848; hg19: chr15-33913487;