chr15-33665926-A-G

Variant names:

• chr15-33665926-A-G
• rs4779628
• NM_001036.6:c.5619+2189A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001036.6(RYR3):​c.5619+2189A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.889 in 152,212 control chromosomes in the GnomAD database, including 60,899 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.89 (60899 hom., cov: 32)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.353
• 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: ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.5619+2189A>G		intron_variant	Intron 36 of 103	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.5619+2189A>G		intron_variant	Intron 36 of 103	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.5619+2189A>G		intron_variant	Intron 36 of 103	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.5619+2189A>G		intron_variant	Intron 36 of 102	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.5619+2189A>G		intron_variant	Intron 36 of 101	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes AF: 0.889 AC: 135286 AN: 152094 Hom.: 60865 Cov.: 32

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.968

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.897

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.945

Gnomad FIN AF: 0.952

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.954

Gnomad OTH AF: 0.897

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.889 AC: 135380 AN: 152212 Hom.: 60899 Cov.: 32 AF XY: 0.892 AC XY: 66372 AN XY: 74414

African (AFR) AF: 0.739 AC: 30649 AN: 41458

American (AMR) AF: 0.929 AC: 14214 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 3114 AN: 3472

East Asian (EAS) AF: 0.929 AC: 4808 AN: 5176

South Asian (SAS) AF: 0.945 AC: 4565 AN: 4830

European-Finnish (FIN) AF: 0.952 AC: 10110 AN: 10618

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.954 AC: 64879 AN: 68036

Other (OTH) AF: 0.898 AC: 1900 AN: 2116

Alfa AF: 0.931 Hom.: 77641

Bravo AF: 0.880

Asia WGS AF: 0.942 AC: 3276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.2
DANN	Benign	0.86
PhyloP100		0.35
Mutation Taster		=100/0	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: rs4779628; hg19: chr15-33958127;