NM_001036.6:c.2770A>G

Variant names:

• chr15-33630030-A-G
• rs199638420
• NM_001036.6:c.2770A>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.2770A>G​(p.Thr924Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,589,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 5.80
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015210718).
• BP6: Variant 15-33630030-A-G is Benign according to our data. Variant chr15-33630030-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461897.

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.2770A>G	p.Thr924Ala	missense	Exon 22 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.2770A>G	p.Thr924Ala	missense	Exon 22 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.2770A>G	p.Thr924Ala	missense	Exon 22 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.2770A>G	p.Thr924Ala	missense	Exon 22 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.2770A>G	p.Thr924Ala	missense	Exon 22 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000635 AC: 142 AN: 223724 AF XY: 0.000675

Gnomad AFR exome AF: 0.000291

Gnomad AMR exome AF: 0.000888

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000146

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000448 AC: 644 AN: 1437598 Hom.: 0 Cov.: 26 AF XY: 0.000468 AC XY: 334 AN XY: 713994

African (AFR) AF: 0.000393 AC: 13 AN: 33106

American (AMR) AF: 0.000849 AC: 36 AN: 42426

Ashkenazi Jewish (ASJ) AF: 0.00607 AC: 156 AN: 25704

East Asian (EAS) AF: 0.00 AC: 0 AN: 39342

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82548

European-Finnish (FIN) AF: 0.000227 AC: 12 AN: 52810

Middle Eastern (MID) AF: 0.00332 AC: 19 AN: 5730

European-Non Finnish (NFE) AF: 0.000314 AC: 344 AN: 1096324

Other (OTH) AF: 0.00106 AC: 63 AN: 59608

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34 AN XY: 74496

African (AFR) AF: 0.000313 AC: 13 AN: 41576

American (AMR) AF: 0.00124 AC: 19 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

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

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

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000717 Hom.: 2

Bravo AF: 0.000684

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.000456 AC: 55

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	1	RYR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.59
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.086
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.46
Sift	Benign	0.93	T
Polyphen		0.27	B
Vest4		0.41
MVP		0.83
MPC		0.25
ClinPred		0.048	T
GERP RS		5.3
Varity_R		0.32
gMVP		0.31
Mutation Taster		=47/53	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: rs199638420; hg19: chr15-33922231; COSMIC: COSV108229567; COSMIC: COSV108229567;