NM_001036.6:c.4396-10C>T

Variant names:

• chr15-33660187-C-T
• rs78825800
• NM_001036.6:c.4396-10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001036.6(RYR3):​c.4396-10C>T 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 1,540,164 control chromosomes in the GnomAD database, including 401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (65 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (336 hom.)
• Consequence: RYR3 NM_001036.6 intron
• Scores: Splicing: ADA: 0.000008042
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0650
• 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: G2P, PanelApp Australia, ClinGen
• congenital myopathy

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-33660187-C-T is Benign according to our data. Variant chr15-33660187-C-T is described in ClinVar as Benign. ClinVar VariationId is 461912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0547 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.4396-10C>T		intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.4396-10C>T		intron	N/A	NP_001230925.1	Q15413-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.4396-10C>T		intron	N/A	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.4396-10C>T		intron	N/A	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.4396-10C>T		intron	N/A	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2471 AN: 152164 Hom.: 63 Cov.: 33

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0573

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0338

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0261 AC: 4062 AN: 155660 AF XY: 0.0224

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0334

Gnomad FIN exome AF: 0.000475

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.0195

GnomAD4 exome AF: 0.00610 AC: 8467 AN: 1387882 Hom.: 336 Cov.: 30 AF XY: 0.00620 AC XY: 4244 AN XY: 684164

African (AFR) AF: 0.0280 AC: 877 AN: 31354

American (AMR) AF: 0.108 AC: 3838 AN: 35470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25008

East Asian (EAS) AF: 0.0320 AC: 1138 AN: 35572

South Asian (SAS) AF: 0.0249 AC: 1966 AN: 78872

European-Finnish (FIN) AF: 0.000528 AC: 26 AN: 49288

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5666

European-Non Finnish (NFE) AF: 0.000140 AC: 150 AN: 1069050

Other (OTH) AF: 0.00804 AC: 463 AN: 57602

GnomAD4 genome AF: 0.0163 AC: 2487 AN: 152282 Hom.: 65 Cov.: 33 AF XY: 0.0169 AC XY: 1261 AN XY: 74458

African (AFR) AF: 0.0293 AC: 1219 AN: 41562

American (AMR) AF: 0.0579 AC: 885 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0337 AC: 174 AN: 5170

South Asian (SAS) AF: 0.0297 AC: 143 AN: 4820

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68032

Other (OTH) AF: 0.0180 AC: 38 AN: 2108

Alfa AF: 0.00856 Hom.: 14

Bravo AF: 0.0218

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)
-	-	1	not provided (1)
-	-	1	RYR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		-0.065
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000080
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: rs78825800; hg19: chr15-33952388;