rs199507912

Positions:

• chr15-33670495-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001036.6(RYR3):​c.5799A>T​(p.Lys1933Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,609,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.67

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15565827).
• BP6: Variant 15-33670495-A-T is Benign according to our data. Variant chr15-33670495-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 530960.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6	c.5799A>T	p.Lys1933Asn	missense_variant	38/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.5799A>T	p.Lys1933Asn	missense_variant	38/104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000353

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000185 AC: 45 AN: 243406 Hom.: 0 AF XY: 0.000227 AC XY: 30 AN XY: 131970

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.000241

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000345

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000297

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000158 AC: 230 AN: 1456840 Hom.: 0 Cov.: 31 AF XY: 0.000159 AC XY: 115 AN XY: 724530

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.000299

Gnomad4 ASJ exome AF: 0.0000775

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74446

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.000174 AC: 21

EpiCase AF: 0.000327

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.5799A>T (p.K1933N) alteration is located in exon 38 (coding exon 38) of the RYR3 gene. This alteration results from a A to T substitution at nucleotide position 5799, causing the lysine (K) at amino acid position 1933 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;.;.;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.7	M;M;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.3	.;D;D;.;.
REVEL	Uncertain	0.54
Sift	Benign	0.096	.;T;T;.;.
Polyphen		0.61	P;P;.;.;.
Vest4		0.35
MutPred		0.26		Loss of methylation at K1933 (P = 0.009);Loss of methylation at K1933 (P = 0.009);Loss of methylation at K1933 (P = 0.009);Loss of methylation at K1933 (P = 0.009);Loss of methylation at K1933 (P = 0.009);
MVP		0.81
MPC		0.21
ClinPred		0.20	T
GERP RS		3.0
Varity_R		0.33
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs199507912; hg19: chr15-33962696;