rs58745096

Variant names:

• chr15-33819768-C-T
• rs58745096
• NM_001036.6:c.10719C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001036.6(RYR3):​c.10719C>T​(p.Asp3573Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,539,658 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (65 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (42 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.460
• 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, ClinGen
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 15-33819768-C-T is Benign according to our data. Variant chr15-33819768-C-T is described in ClinVar as Benign. ClinVar VariationId is 461829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (2128/152210) while in subpopulation AFR AF = 0.0482 (2003/41516). AF 95% confidence interval is 0.0465. There are 65 homozygotes in GnomAd4. There are 1022 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 65 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.10719C>T	p.Asp3573Asp	synonymous	Exon 77 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.10704C>T	p.Asp3568Asp	synonymous	Exon 76 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.10719C>T	p.Asp3573Asp	synonymous	Exon 77 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.10716C>T	p.Asp3572Asp	synonymous	Exon 77 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.10704C>T	p.Asp3568Asp	synonymous	Exon 76 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2118 AN: 152092 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00300 AC: 706 AN: 235092 AF XY: 0.00204

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.00146 AC: 2026 AN: 1387448 Hom.: 42 Cov.: 29 AF XY: 0.00124 AC XY: 850 AN XY: 687516

African (AFR) AF: 0.0505 AC: 1606 AN: 31800

American (AMR) AF: 0.00207 AC: 87 AN: 41994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24332

East Asian (EAS) AF: 0.00 AC: 0 AN: 37530

South Asian (SAS) AF: 0.0000432 AC: 3 AN: 69466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49430

Middle Eastern (MID) AF: 0.00386 AC: 21 AN: 5444

European-Non Finnish (NFE) AF: 0.0000897 AC: 96 AN: 1070800

Other (OTH) AF: 0.00376 AC: 213 AN: 56652

GnomAD4 genome AF: 0.0140 AC: 2128 AN: 152210 Hom.: 65 Cov.: 32 AF XY: 0.0137 AC XY: 1022 AN XY: 74432

African (AFR) AF: 0.0482 AC: 2003 AN: 41516

American (AMR) AF: 0.00516 AC: 79 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68002

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00570 Hom.: 15

Bravo AF: 0.0159

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.34
CADD	Benign	0.58
DANN	Benign	0.49
PhyloP100		-0.46
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs58745096; hg19: chr15-34111969; COSMIC: COSV66781811; COSMIC: COSV66781811;