rs55650127

Variant names:

• chr15-33788387-C-T
• rs55650127
• NM_001036.6:c.9759C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-33788387-C-T
• chr15-33788387-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001036.6(RYR3):​c.9759C>T​(p.Asp3253Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,613,850 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (19 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.07
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 15-33788387-C-T is Benign according to our data. Variant chr15-33788387-C-T is described in ClinVar as Benign. ClinVar VariationId is 461989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0038 (5560/1461602) while in subpopulation MID AF = 0.0281 (162/5768). AF 95% confidence interval is 0.0246. There are 19 homozygotes in GnomAdExome4. There are 2782 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.9759C>T	p.Asp3253Asp	synonymous	Exon 67 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.9759C>T	p.Asp3253Asp	synonymous	Exon 67 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.9759C>T	p.Asp3253Asp	synonymous	Exon 67 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.9756C>T	p.Asp3252Asp	synonymous	Exon 67 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.9759C>T	p.Asp3253Asp	synonymous	Exon 67 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 809 AN: 152130 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00418 AC: 1042 AN: 249120 AF XY: 0.00414

Gnomad AFR exome AF: 0.00962

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00484

Gnomad OTH exome AF: 0.00728

GnomAD4 exome AF: 0.00380 AC: 5560 AN: 1461602 Hom.: 19 Cov.: 32 AF XY: 0.00383 AC XY: 2782 AN XY: 727102

African (AFR) AF: 0.0111 AC: 370 AN: 33476

American (AMR) AF: 0.00445 AC: 199 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00551 AC: 144 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00274 AC: 236 AN: 86256

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53402

Middle Eastern (MID) AF: 0.0281 AC: 162 AN: 5768

European-Non Finnish (NFE) AF: 0.00372 AC: 4140 AN: 1111782

Other (OTH) AF: 0.00461 AC: 278 AN: 60366

GnomAD4 genome AF: 0.00532 AC: 810 AN: 152248 Hom.: 4 Cov.: 33 AF XY: 0.00501 AC XY: 373 AN XY: 74448

African (AFR) AF: 0.00944 AC: 392 AN: 41528

American (AMR) AF: 0.00484 AC: 74 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3466

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

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00412 AC: 280 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00544 Hom.: 1

Bravo AF: 0.00568

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00652

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.095
DANN	Benign	0.52
PhyloP100		-1.1
Mutation Taster		=96/4	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: rs55650127; hg19: chr15-34080588; COSMIC: COSV66780833;