rs371629185

chr15-33821578-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001036.6(RYR3):c.10971C>T(p.Asn3657=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,613,952 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (3 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.164

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 15-33821578-C-T is Benign according to our data. Variant chr15-33821578-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 461836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.164 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.10971C>T	p.Asn3657=	synonymous_variant	80/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.10971C>T	p.Asn3657=	synonymous_variant	80/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000365 AC: 91 AN: 249182 Hom.: 3 AF XY: 0.000407 AC XY: 55 AN XY: 135170

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000548 AC: 801 AN: 1461686 Hom.: 3 Cov.: 32 AF XY: 0.000569 AC XY: 414 AN XY: 727124

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000596

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74454

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000507 Hom.: 1

Bravo AF: 0.000348

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

RYR3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	5.3
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs371629185; hg19: chr15-34113779; COSMIC: COSV66780561; COSMIC: COSV66780561;