NM_001036.6:c.7490A>G

Variant names:

• chr15-33736300-A-G
• rs61996331
• NM_001036.6:c.7490A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001036.6(RYR3):​c.7490A>G​(p.Asn2497Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 1,612,504 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.33
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008216709).
• BP6: Variant 15-33736300-A-G is Benign according to our data. Variant chr15-33736300-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461949.

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.7490A>G	p.Asn2497Ser	missense	Exon 49 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.7490A>G	p.Asn2497Ser	missense	Exon 49 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.7490A>G	p.Asn2497Ser	missense	Exon 49 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.7487A>G	p.Asn2496Ser	missense	Exon 49 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.7490A>G	p.Asn2497Ser	missense	Exon 49 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000457 AC: 113 AN: 247374 AF XY: 0.000403

Gnomad AFR exome AF: 0.00692

Gnomad AMR exome AF: 0.0000874

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000165 AC: 241 AN: 1460190 Hom.: 1 Cov.: 29 AF XY: 0.000150 AC XY: 109 AN XY: 726266

African (AFR) AF: 0.00607 AC: 203 AN: 33460

American (AMR) AF: 0.000157 AC: 7 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000816 AC: 7 AN: 85812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111212

Other (OTH) AF: 0.000282 AC: 17 AN: 60332

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74476

African (AFR) AF: 0.00630 AC: 262 AN: 41576

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000675 Hom.: 0

Bravo AF: 0.00179

ESP6500AA AF: 0.00578 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000513 AC: 62

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.54	N
PhyloP100		3.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.23
Sift	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.29
MVP		0.49
MPC		0.14
ClinPred		0.013	T
GERP RS		2.4
Varity_R		0.071
gMVP		0.13
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61996331; hg19: chr15-34028501;