chr15-33621286-A-C

Variant names:

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

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>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 152,196 control chromosomes in the GnomAD database, including 72 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 0.019 (72 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.2358-2521A>C		intron_variant	Intron 19 of 103	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.2358-2521A>C		intron_variant	Intron 19 of 103	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.2358-2521A>C		intron_variant	Intron 19 of 103	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.2358-2521A>C		intron_variant	Intron 19 of 102	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.2358-2521A>C		intron_variant	Intron 19 of 101	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2871 AN: 152078 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.0143

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

GnomAD4 genome AF: 0.0190 AC: 2890 AN: 152196 Hom.: 72 Cov.: 32 AF XY: 0.0183 AC XY: 1360 AN XY: 74396

African (AFR) AF: 0.0587 AC: 2438 AN: 41540

American (AMR) AF: 0.0166 AC: 254 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10572

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 68018

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00 Hom.: 5343

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.11
DANN	Benign	0.72
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism

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;