NM_001036.6:c.12516G>C

Variant names:

• chr15-33838496-G-C
• rs75286462
• NM_001036.6:c.12516G>C

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.12516G>C​(p.Val4172Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,613,970 control chromosomes in the GnomAD database, including 1,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (160 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1288 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.578
• Publications: 3 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 15-33838496-G-C is Benign according to our data. Variant chr15-33838496-G-C is described in ClinVar as Benign. ClinVar VariationId is 461852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.578 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0322 (4902/152292) while in subpopulation NFE AF = 0.0385 (2619/68024). AF 95% confidence interval is 0.0373. There are 160 homozygotes in GnomAd4. There are 2623 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 160 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.12516G>C	p.Val4172Val	synonymous	Exon 89 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.12501G>C	p.Val4167Val	synonymous	Exon 88 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.12516G>C	p.Val4172Val	synonymous	Exon 89 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.12513G>C	p.Val4171Val	synonymous	Exon 89 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.12501G>C	p.Val4167Val	synonymous	Exon 88 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4906 AN: 152174 Hom.: 160 Cov.: 32

Gnomad AFR AF: 0.00695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.0350 AC: 8720 AN: 248932 AF XY: 0.0355

Gnomad AFR exome AF: 0.00672

Gnomad AMR exome AF: 0.0216

Gnomad ASJ exome AF: 0.0313

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0373 AC: 54460 AN: 1461678 Hom.: 1288 Cov.: 33 AF XY: 0.0363 AC XY: 26428 AN XY: 727120

African (AFR) AF: 0.00526 AC: 176 AN: 33478

American (AMR) AF: 0.0223 AC: 998 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 850 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0140 AC: 1207 AN: 86258

European-Finnish (FIN) AF: 0.110 AC: 5882 AN: 53400

Middle Eastern (MID) AF: 0.0156 AC: 90 AN: 5768

European-Non Finnish (NFE) AF: 0.0388 AC: 43148 AN: 1111850

Other (OTH) AF: 0.0349 AC: 2107 AN: 60370

GnomAD4 genome AF: 0.0322 AC: 4902 AN: 152292 Hom.: 160 Cov.: 32 AF XY: 0.0352 AC XY: 2623 AN XY: 74456

African (AFR) AF: 0.00693 AC: 288 AN: 41570

American (AMR) AF: 0.0285 AC: 436 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4832

European-Finnish (FIN) AF: 0.124 AC: 1316 AN: 10592

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0385 AC: 2619 AN: 68024

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0263 Hom.: 25

Bravo AF: 0.0257

Asia WGS AF: 0.00837 AC: 30 AN: 3478

EpiCase AF: 0.0367

EpiControl AF: 0.0408

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.66
DANN	Benign	0.56
PhyloP100		0.58
PromoterAI		0.020	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs75286462; hg19: chr15-34130697; COSMIC: COSV66789944; COSMIC: COSV66789944;