rs200724716

Variant names:

• chr15-33543623-A-G
• rs200724716
• NM_001036.6:c.648A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-33543623-A-G
• chr15-33543623-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_001036.6(RYR3):​c.648A>G​(p.Gly216Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000334 in 1,586,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RYR3 NM_001036.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002767
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.156
• 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: 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 (BayesDel_noAF=-0.45).
• BP6: Variant 15-33543623-A-G is Benign according to our data. Variant chr15-33543623-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 566501.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.156 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.648A>G	p.Gly216Gly	splice_region_variant, synonymous_variant	Exon 8 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.648A>G	p.Gly216Gly	splice_region_variant, synonymous_variant	Exon 8 of 104	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.648A>G	p.Gly216Gly	splice_region_variant, synonymous_variant	Exon 8 of 104	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.648A>G	p.Gly216Gly	splice_region_variant, synonymous_variant	Exon 8 of 103	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.648A>G	p.Gly216Gly	splice_region_variant, synonymous_variant	Exon 8 of 102	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

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: 0.00191

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248916 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000166

GnomAD4 exome AF: 0.0000119 AC: 17 AN: 1434520 Hom.: 0 Cov.: 27 AF XY: 0.00000978 AC XY: 7 AN XY: 715652

African (AFR) AF: 0.0000607 AC: 2 AN: 32936

American (AMR) AF: 0.000202 AC: 9 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39564

South Asian (SAS) AF: 0.00 AC: 0 AN: 85748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087218

Other (OTH) AF: 0.0000842 AC: 5 AN: 59384

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74466

African (AFR) AF: 0.0000241 AC: 1 AN: 41570

American (AMR) AF: 0.00203 AC: 31 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.0000848 Hom.: 0

Bravo AF: 0.000654

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.6
DANN	Benign	0.78
PhyloP100		-0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.010		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: rs200724716; hg19: chr15-33835824;