chr15-33757613-A-C

Variant names:

• chr15-33757613-A-C
• rs148404688
• NM_001036.6:c.8705+17A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001036.6(RYR3):​c.8705+17A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00711 in 1,606,702 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (53 hom.)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0420
• 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
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-33757613-A-C is Benign according to our data. Variant chr15-33757613-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 445856.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.8705+17A>C		intron_variant	Intron 60 of 103	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.8705+17A>C		intron_variant	Intron 60 of 103	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 756 AN: 152118 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00820

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00519 AC: 1225 AN: 236164 AF XY: 0.00556

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.000308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.00834

Gnomad OTH exome AF: 0.00292

GnomAD4 exome AF: 0.00733 AC: 10661 AN: 1454468 Hom.: 53 Cov.: 31 AF XY: 0.00718 AC XY: 5187 AN XY: 722498

African (AFR) AF: 0.00108 AC: 36 AN: 33354

American (AMR) AF: 0.000685 AC: 30 AN: 43802

Ashkenazi Jewish (ASJ) AF: 0.000771 AC: 20 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.00582 AC: 490 AN: 84204

European-Finnish (FIN) AF: 0.00579 AC: 307 AN: 53054

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5758

European-Non Finnish (NFE) AF: 0.00857 AC: 9506 AN: 1108752

Other (OTH) AF: 0.00444 AC: 267 AN: 60160

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152234 Hom.: 4 Cov.: 32 AF XY: 0.00496 AC XY: 369 AN XY: 74432

African (AFR) AF: 0.00147 AC: 61 AN: 41528

American (AMR) AF: 0.00163 AC: 25 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4822

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00820 AC: 558 AN: 68012

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00509 Hom.: 0

Bravo AF: 0.00425

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.41
PhyloP100		0.042
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs148404688; hg19: chr15-34049814;