Genetic Variant NM_001036.6:c.3942-130C>T (chr15-33647294-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001036.6(RYR3):c.3942-130C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 678,702 control chromosomes in the GnomAD database, including 16,812 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 0.21 ( 3331 hom., cov: 32)

Exomes 𝑓: 0.22 ( 13481 hom. )

Consequence

RYR3
NM_001036.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.451

Publications

5 publications found

Variant links:

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

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.3942-130C>T		intron_variant	Intron 29 of 103	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 link	c.3942-130C>T		intron_variant	Intron 29 of 103	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31355

AN:

152022

Hom.:

3334

Cov.:

show subpopulations

Gnomad AFR

AF:

0.189

Gnomad AMI

AF:

0.0844

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.288

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.215

Gnomad OTH

AF:

0.233

GnomAD4 exome

AF:

0.219

AC:

115362

AN:

526562

Hom.:

13481

AF XY:

0.221

AC XY:

62161

AN XY:

281230

show subpopulations

African (AFR)

AF:

0.184

AC:

2570

AN:

13940

American (AMR)

AF:

0.157

AC:

3718

AN:

23708

Ashkenazi Jewish (ASJ)

AF:

0.309

AC:

4660

AN:

15068

East Asian (EAS)

AF:

0.341

AC:

10966

AN:

32140

South Asian (SAS)

AF:

0.228

AC:

11213

AN:

49224

European-Finnish (FIN)

AF:

0.158

AC:

6979

AN:

44212

Middle Eastern (MID)

AF:

0.294

AC:

1099

AN:

3740

European-Non Finnish (NFE)

AF:

0.215

AC:

67909

AN:

315900

Other (OTH)

AF:

0.218

AC:

6248

AN:

28630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

4211

8422

12632

16843

21054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

662

1324

1986

2648

3310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.206

AC:

31356

AN:

152140

Hom.:

3331

Cov.:

AF XY:

0.205

AC XY:

15262

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.189

AC:

7842

AN:

41510

American (AMR)

AF:

0.192

AC:

2938

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

1055

AN:

3466

East Asian (EAS)

AF:

0.288

AC:

1485

AN:

5154

South Asian (SAS)

AF:

0.227

AC:

1095

AN:

4820

European-Finnish (FIN)

AF:

0.159

AC:

1689

AN:

10600

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.215

AC:

14608

AN:

67986

Other (OTH)

AF:

0.231

AC:

487

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1280

2560

3840

5120

6400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.217

Hom.:

7329

Bravo

AF:

0.205

Asia WGS

AF:

0.238

AC:

828

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over