rs61996329

Variant names:

• chr15-33701041-T-C
• rs61996329
• NM_001036.6:c.6444T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-33701041-T-C
• chr15-33701041-T-A
• chr15-33701041-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001036.6(RYR3):​c.6444T>C​(p.Asn2148Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,306 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (30 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.245
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 15-33701041-T-C is Benign according to our data. Variant chr15-33701041-T-C is described in ClinVar as Benign. ClinVar VariationId is 461935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.245 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1727/152224) while in subpopulation AFR AF = 0.0391 (1625/41528). AF 95% confidence interval is 0.0375. There are 22 homozygotes in GnomAd4. There are 823 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.6444T>C	p.Asn2148Asn	synonymous	Exon 42 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.6444T>C	p.Asn2148Asn	synonymous	Exon 42 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.6444T>C	p.Asn2148Asn	synonymous	Exon 42 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.6444T>C	p.Asn2148Asn	synonymous	Exon 42 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.6444T>C	p.Asn2148Asn	synonymous	Exon 42 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1728 AN: 152106 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

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: 0.000103

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00276 AC: 685 AN: 248310 AF XY: 0.00227

Gnomad AFR exome AF: 0.0388

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00112 AC: 1638 AN: 1461082 Hom.: 30 Cov.: 30 AF XY: 0.00101 AC XY: 731 AN XY: 726722

African (AFR) AF: 0.0387 AC: 1295 AN: 33464

American (AMR) AF: 0.00244 AC: 109 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111628

Other (OTH) AF: 0.00255 AC: 154 AN: 60344

GnomAD4 genome AF: 0.0113 AC: 1727 AN: 152224 Hom.: 22 Cov.: 32 AF XY: 0.0111 AC XY: 823 AN XY: 74434

African (AFR) AF: 0.0391 AC: 1625 AN: 41528

American (AMR) AF: 0.00477 AC: 73 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00942 Hom.: 26

Bravo AF: 0.0127

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

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
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.63
DANN	Benign	0.65
PhyloP100		-0.24
Mutation Taster		=100/0	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: rs61996329; hg19: chr15-33993242;