rs61996338

Variant names:

• chr15-33788314-C-T
• rs61996338
• NM_001036.6:c.9686C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001036.6(RYR3):​c.9686C>T​(p.Thr3229Met) variant causes a missense change. The variant allele was found at a frequency of 0.00309 in 1,613,936 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (54 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.10
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032494962).
• BP6: Variant 15-33788314-C-T is Benign according to our data. Variant chr15-33788314-C-T is described in ClinVar as Benign. ClinVar VariationId is 461988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1994/152250) while in subpopulation AFR AF = 0.0427 (1772/41542). AF 95% confidence interval is 0.041. There are 41 homozygotes in GnomAd4. There are 913 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 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.9686C>T	p.Thr3229Met	missense	Exon 67 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.9686C>T	p.Thr3229Met	missense	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.9686C>T	p.Thr3229Met	missense	Exon 67 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.9683C>T	p.Thr3228Met	missense	Exon 67 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.9686C>T	p.Thr3229Met	missense	Exon 67 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1991 AN: 152132 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00904

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00425 AC: 1058 AN: 249054 AF XY: 0.00335

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.00663

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000807

Gnomad OTH exome AF: 0.00628

GnomAD4 exome AF: 0.00205 AC: 2990 AN: 1461686 Hom.: 54 Cov.: 32 AF XY: 0.00193 AC XY: 1400 AN XY: 727130

African (AFR) AF: 0.0462 AC: 1546 AN: 33480

American (AMR) AF: 0.00729 AC: 326 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5768

European-Non Finnish (NFE) AF: 0.000674 AC: 749 AN: 1111852

Other (OTH) AF: 0.00475 AC: 287 AN: 60374

GnomAD4 genome AF: 0.0131 AC: 1994 AN: 152250 Hom.: 41 Cov.: 33 AF XY: 0.0123 AC XY: 913 AN XY: 74442

African (AFR) AF: 0.0427 AC: 1772 AN: 41542

American (AMR) AF: 0.00903 AC: 138 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68020

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00580 Hom.: 40

Bravo AF: 0.0156

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0401 AC: 164

ESP6500EA AF: 0.000477 AC: 4

ExAC AF: 0.00476 AC: 576

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00154

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
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Benign	0.80
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		5.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Polyphen		0.46	P
Vest4		0.31
MVP		0.41
MPC		0.21
ClinPred		0.024	T
GERP RS		2.4
Varity_R		0.017
gMVP		0.37
Mutation Taster		=69/31	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: rs61996338; hg19: chr15-34080515; COSMIC: COSV66783176;