NM_001036.6:c.8542G>A

Variant names:

• chr15-33756332-G-A
• rs190035689
• NM_001036.6:c.8542G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001036.6(RYR3):​c.8542G>A​(p.Glu2848Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,581,714 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 7.81
• Publications: 4 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: ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010458052).
• BP6: Variant 15-33756332-G-A is Benign according to our data. Variant chr15-33756332-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 461969.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.8542G>A	p.Glu2848Lys	missense	Exon 59 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.8542G>A	p.Glu2848Lys	missense	Exon 59 of 103	NP_001230925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.8542G>A	p.Glu2848Lys	missense	Exon 59 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.8539G>A	p.Glu2847Lys	missense	Exon 59 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.8542G>A	p.Glu2848Lys	missense	Exon 59 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00396

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000317 AC: 64 AN: 201822 AF XY: 0.000233

Gnomad AFR exome AF: 0.00467

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000343

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.000190 AC: 271 AN: 1429402 Hom.: 0 Cov.: 30 AF XY: 0.000167 AC XY: 118 AN XY: 707400

African (AFR) AF: 0.00448 AC: 147 AN: 32838

American (AMR) AF: 0.000175 AC: 7 AN: 39888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25528

East Asian (EAS) AF: 0.00 AC: 0 AN: 38396

South Asian (SAS) AF: 0.00 AC: 0 AN: 81200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000913 AC: 100 AN: 1094862

Other (OTH) AF: 0.000287 AC: 17 AN: 59326

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74464

African (AFR) AF: 0.00399 AC: 166 AN: 41578

American (AMR) AF: 0.000327 AC: 5 AN: 15302

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000588 Hom.: 2

Bravo AF: 0.00133

ESP6500AA AF: 0.00349 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000308 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)
-	-	1	RYR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.46
Sift	Benign	0.24	T
Polyphen		0.86	P
Vest4		0.49
MVP		0.62
MPC		0.32
ClinPred		0.030	T
GERP RS		5.2
Varity_R		0.55
gMVP		0.27
Mutation Taster		=48/52	disease causing

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: rs190035689; hg19: chr15-34048533; COSMIC: COSV66809431; COSMIC: COSV66809431;