NM_001036.6:c.4473C>T

Variant names:

• chr15-33660274-C-T
• rs61996324
• NM_001036.6:c.4473C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001036.6(RYR3):​c.4473C>T​(p.Asp1491Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,558,636 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (13 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 15-33660274-C-T is Benign according to our data. Variant chr15-33660274-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 461913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.4473C>T	p.Asp1491Asp	synonymous	Exon 34 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.4473C>T	p.Asp1491Asp	synonymous	Exon 34 of 103	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.4473C>T	p.Asp1491Asp	synonymous	Exon 34 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.4473C>T	p.Asp1491Asp	synonymous	Exon 34 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.4473C>T	p.Asp1491Asp	synonymous	Exon 34 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 387 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00218 AC: 363 AN: 166426 AF XY: 0.00226

Gnomad AFR exome AF: 0.000917

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.000346

Gnomad EAS exome AF: 0.0000869

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00391

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00370 AC: 5207 AN: 1406306 Hom.: 13 Cov.: 32 AF XY: 0.00366 AC XY: 2539 AN XY: 694240

African (AFR) AF: 0.000501 AC: 16 AN: 31940

American (AMR) AF: 0.000908 AC: 33 AN: 36324

Ashkenazi Jewish (ASJ) AF: 0.000158 AC: 4 AN: 25262

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36176

South Asian (SAS) AF: 0.00135 AC: 107 AN: 79510

European-Finnish (FIN) AF: 0.00167 AC: 83 AN: 49774

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5710

European-Non Finnish (NFE) AF: 0.00444 AC: 4814 AN: 1083192

Other (OTH) AF: 0.00245 AC: 143 AN: 58418

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74482

African (AFR) AF: 0.000890 AC: 37 AN: 41578

American (AMR) AF: 0.00385 AC: 59 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00385 AC: 262 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00332 Hom.: 1

Bravo AF: 0.00267

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.66
CADD	Benign	0.54
DANN	Benign	0.71
PhyloP100		-1.8
Mutation Taster		=91/9	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: rs61996324; hg19: chr15-33952475; COSMIC: COSV66799902;