15-33311062-A-G

Variant names:

• chr15-33311062-A-G
• rs562147027
• NM_001036.6:c.17A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001036.6(RYR3):​c.17A>G​(p.Glu6Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000191 in 1,582,534 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 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.92

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009333372).
• BP6: Variant 15-33311062-A-G is Benign according to our data. Variant chr15-33311062-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 531143.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.17A>G	p.Glu6Gly	missense_variant	Exon 1 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.17A>G	p.Glu6Gly	missense_variant	Exon 1 of 104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00156

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000454 AC: 100 AN: 220478 Hom.: 0 AF XY: 0.000504 AC XY: 61 AN XY: 121102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000327

Gnomad ASJ exome AF: 0.00845

Gnomad EAS exome AF: 0.000708

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000888

Gnomad OTH exome AF: 0.000390

GnomAD4 exome AF: 0.000183 AC: 262 AN: 1430476 Hom.: 0 Cov.: 30 AF XY: 0.000184 AC XY: 131 AN XY: 711212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000242

Gnomad4 ASJ exome AF: 0.00757

Gnomad4 EAS exome AF: 0.000555

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000255

Gnomad4 OTH exome AF: 0.000356

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00156

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000238

ExAC AF: 0.000381 AC: 46

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Apr 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.17A>G (p.E6G) alteration is located in exon 1 (coding exon 1) of the RYR3 gene. This alteration results from a A to G substitution at nucleotide position 17, causing the glutamic acid (E) at amino acid position 6 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy Benign:1

Feb 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.;.;.
Eigen	Benign	0.011
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T;T;T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.0093	T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.0	L;L;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.81	.;N;N;.;.
REVEL	Benign	0.29
Sift	Benign	0.83	.;T;T;.;.
Polyphen		0.32	B;B;.;.;.
Vest4		0.49
MVP		0.47
MPC		0.21
ClinPred		0.099	T
GERP RS		5.2
Varity_R		0.20
gMVP		0.29

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: rs562147027; hg19: chr15-33603263; COSMIC: COSV105326333; COSMIC: COSV105326333;