dbSNP rs113699058: RYR3:c.6134+9T>C (chr15-33696500-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001036.6(RYR3):c.6134+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,613,792 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 8 hom., cov: 31)

Exomes 𝑓: 0.00091 ( 16 hom. )

Consequence

RYR3
NM_001036.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.527

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 15-33696500-T-C is Benign according to our data. Variant chr15-33696500-T-C is described in ClinVar as Benign. ClinVar VariationId is 461934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00643 (980/152308) while in subpopulation AFR AF = 0.022 (916/41578). AF 95% confidence interval is 0.0208. There are 8 homozygotes in GnomAd4. There are 464 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.6134+9T>C		intron_variant	Intron 39 of 103	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR3	ENST00000634891.2 link	c.6134+9T>C	intron_variant	Intron 39 of 103	1	NM_001036.6	ENSP00000489262.1	Q15413-1
RYR3	ENST00000389232.9 link	c.6134+9T>C	intron_variant	Intron 39 of 103	5		ENSP00000373884.5	A0A0X1KG73
RYR3	ENST00000415757.7 link	c.6134+9T>C	intron_variant	Intron 39 of 102	2		ENSP00000399610.3	Q15413-2
RYR3	ENST00000634418.1 link	c.6134+9T>C	intron_variant	Intron 39 of 101	5		ENSP00000489529.1	A0A0U1RRH1

Frequencies

GnomAD3 genomes

AF:

0.00636

AC:

968

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00199

AC:

492

AN:

247676

AF XY:

0.00167

show subpopulations

Gnomad AFR exome

AF:

0.0213

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.00230

Gnomad EAS exome

AF:

0.00545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000985

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000907

AC:

1326

AN:

1461484

Hom.:

Cov.:

AF XY:

0.000768

AC XY:

558

AN XY:

727012

show subpopulations

African (AFR)

AF:

0.0253

AC:

847

AN:

33474

American (AMR)

AF:

0.000626

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26110

East Asian (EAS)

AF:

0.00373

AC:

148

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000648

AC:

AN:

1111728

Other (OTH)

AF:

0.00244

AC:

147

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00643

AC:

980

AN:

152308

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

464

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0220

AC:

916

AN:

41578

American (AMR)

AF:

0.00118

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00348

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68022

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

138

184

230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00534

Hom.:

Bravo

AF:

0.00740

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Mar 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.54

(source)

DANN

Benign

0.24

PhyloP100

-0.53

Mutation Taster

=100/0

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over