NM_001036.6:c.1110C>T

Variant names:

• chr15-33562974-C-T
• rs16972317
• NM_001036.6:c.1110C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001036.6(RYR3):​c.1110C>T​(p.Asp370Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00619 in 1,611,850 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (161 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (167 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77
• Publications: 5 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=-0.3).
• BP6: Variant 15-33562974-C-T is Benign according to our data. Variant chr15-33562974-C-T is described in ClinVar as Benign. ClinVar VariationId is 461837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0851 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.1110C>T	p.Asp370Asp	synonymous	Exon 11 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.1110C>T	p.Asp370Asp	synonymous	Exon 11 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.1110C>T	p.Asp370Asp	synonymous	Exon 11 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.1110C>T	p.Asp370Asp	synonymous	Exon 11 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.1110C>T	p.Asp370Asp	synonymous	Exon 11 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4007 AN: 152066 Hom.: 161 Cov.: 32

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.00829

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00920 AC: 2276 AN: 247386 AF XY: 0.00734

Gnomad AFR exome AF: 0.0918

Gnomad AMR exome AF: 0.00450

Gnomad ASJ exome AF: 0.0418

Gnomad EAS exome AF: 0.00844

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000792

Gnomad OTH exome AF: 0.00602

GnomAD4 exome AF: 0.00409 AC: 5969 AN: 1459666 Hom.: 167 Cov.: 31 AF XY: 0.00368 AC XY: 2673 AN XY: 725824

African (AFR) AF: 0.0913 AC: 3051 AN: 33410

American (AMR) AF: 0.00515 AC: 229 AN: 44480

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 1036 AN: 26104

East Asian (EAS) AF: 0.0109 AC: 433 AN: 39640

South Asian (SAS) AF: 0.000385 AC: 33 AN: 85782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5760

European-Non Finnish (NFE) AF: 0.000520 AC: 578 AN: 1110816

Other (OTH) AF: 0.00949 AC: 572 AN: 60286

GnomAD4 genome AF: 0.0264 AC: 4014 AN: 152184 Hom.: 161 Cov.: 32 AF XY: 0.0249 AC XY: 1856 AN XY: 74418

African (AFR) AF: 0.0875 AC: 3629 AN: 41484

American (AMR) AF: 0.00772 AC: 118 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 140 AN: 3468

East Asian (EAS) AF: 0.00831 AC: 43 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68018

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0113 Hom.: 132

Bravo AF: 0.0303

Asia WGS AF: 0.00808 AC: 28 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.51
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs16972317; hg19: chr15-33855175; COSMIC: COSV66797962;