NM_001036.6:c.2357+2052A>C

Variant names:

• chr15-33615427-A-C
• rs4238566
• NM_001036.6:c.2357+2052A>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.2357+2052A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 152,108 control chromosomes in the GnomAD database, including 33,151 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 0.65 (33151 hom., cov: 33)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.706
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.2357+2052A>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.2357+2052A>C		intron_variant	Intron 19 of 103	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.2357+2052A>C		intron_variant	Intron 19 of 103	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.2357+2052A>C		intron_variant	Intron 19 of 102	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.2357+2052A>C		intron_variant	Intron 19 of 101	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98392 AN: 151990 Hom.: 33144 Cov.: 33

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.809

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.670

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

GnomAD4 genome AF: 0.647 AC: 98432 AN: 152108 Hom.: 33151 Cov.: 33 AF XY: 0.648 AC XY: 48182 AN XY: 74342

African (AFR) AF: 0.476 AC: 19748 AN: 41502

American (AMR) AF: 0.660 AC: 10095 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.809 AC: 2804 AN: 3468

East Asian (EAS) AF: 0.421 AC: 2170 AN: 5158

South Asian (SAS) AF: 0.663 AC: 3191 AN: 4810

European-Finnish (FIN) AF: 0.734 AC: 7754 AN: 10570

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.742 AC: 50465 AN: 68000

Other (OTH) AF: 0.669 AC: 1412 AN: 2112

Alfa AF: 0.713 Hom.: 109263

Bravo AF: 0.632

Asia WGS AF: 0.532 AC: 1851 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.4
DANN	Benign	0.17
PhyloP100		0.71
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: rs4238566; hg19: chr15-33907628;