15-33603372-C-T

Variant names:

• chr15-33603372-C-T
• rs75782410
• NM_001036.6:c.2164+8C>T

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.2164+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,549,158 control chromosomes in the GnomAD database, including 519 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 0.017 (32 hom., cov: 31)
  • Exomes 𝑓: 0.024 (487 hom.)
• Consequence: RYR3 NM_001036.6 splice_region, intron
• Scores: Splicing: ADA: 0.00006225
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.720
• Publications: 1 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=-0.69).
• BP6: Variant 15-33603372-C-T is Benign according to our data. Variant chr15-33603372-C-T is described in ClinVar as Benign. ClinVar VariationId is 461888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2635/152220) while in subpopulation NFE AF = 0.0262 (1785/68018). AF 95% confidence interval is 0.0252. There are 32 homozygotes in GnomAd4. There are 1259 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 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.2164+8C>T		splice_region intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.2164+8C>T		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.2164+8C>T		splice_region intron	N/A	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.2164+8C>T		splice_region intron	N/A	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.2164+8C>T		splice_region intron	N/A	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2637 AN: 152102 Hom.: 32 Cov.: 31

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00913

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0189 AC: 3813 AN: 201828 AF XY: 0.0188

Gnomad AFR exome AF: 0.00458

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.00800

Gnomad EAS exome AF: 0.0000604

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0274

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0243 AC: 33962 AN: 1396938 Hom.: 487 Cov.: 31 AF XY: 0.0240 AC XY: 16510 AN XY: 688160

African (AFR) AF: 0.00461 AC: 145 AN: 31458

American (AMR) AF: 0.0132 AC: 465 AN: 35326

Ashkenazi Jewish (ASJ) AF: 0.00810 AC: 179 AN: 22096

East Asian (EAS) AF: 0.000103 AC: 4 AN: 38736

South Asian (SAS) AF: 0.0107 AC: 812 AN: 75962

European-Finnish (FIN) AF: 0.0209 AC: 1070 AN: 51290

Middle Eastern (MID) AF: 0.00551 AC: 30 AN: 5448

European-Non Finnish (NFE) AF: 0.0278 AC: 30045 AN: 1079132

Other (OTH) AF: 0.0211 AC: 1212 AN: 57490

GnomAD4 genome AF: 0.0173 AC: 2635 AN: 152220 Hom.: 32 Cov.: 31 AF XY: 0.0169 AC XY: 1259 AN XY: 74416

African (AFR) AF: 0.00568 AC: 236 AN: 41534

American (AMR) AF: 0.0164 AC: 250 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00893 AC: 43 AN: 4814

European-Finnish (FIN) AF: 0.0181 AC: 192 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0262 AC: 1785 AN: 68018

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

Alfa AF: 0.0232 Hom.: 51

Bravo AF: 0.0160

Asia WGS AF: 0.00693 AC: 26 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	10
DANN	Benign	0.61
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.0
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: rs75782410; hg19: chr15-33895573;