Genetic Variant NM_001035.3:c.11092-11dupT (chr1-237742270-C-CT) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001035.3(RYR2):c.11092-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,162,062 control chromosomes in the GnomAD database, including 502 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 398 hom., cov: 26)

Exomes 𝑓: 0.11 ( 104 hom. )

Consequence

RYR2
NM_001035.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0580

Variant links:

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

RYR2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 1-237742270-C-CT is Benign according to our data. Variant chr1-237742270-C-CT is described in ClinVar as [Likely_benign]. Clinvar id is 177986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3 link	c.11092-11dupT		intron_variant	Intron 79 of 104	ENST00000366574.7	NP_001026.2	Q92736-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR2	ENST00000366574.7 link	c.11092-26_11092-25insT	intron_variant	Intron 79 of 104	1	NM_001035.3	ENSP00000355533.2	Q92736-1
RYR2	ENST00000661330.1 link	c.898-26_898-25insT	intron_variant	Intron 10 of 11			ENSP00000499393.2	A0A590UJF6
RYR2	ENST00000609119.2 link	n.2127-26_2127-25insT	intron_variant	Intron 77 of 103	5		ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes

AF:

0.0749

AC:

10375

AN:

138484

Hom.:

398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0467

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0786

Gnomad ASJ

AF:

0.0525

Gnomad EAS

AF:

0.0398

Gnomad SAS

AF:

0.0972

Gnomad FIN

AF:

0.0666

Gnomad MID

AF:

0.0811

Gnomad NFE

AF:

0.0931

Gnomad OTH

AF:

0.0756

GnomAD4 exome

AF:

0.111

AC:

113383

AN:

1023570

Hom.:

104

Cov.:

AF XY:

0.109

AC XY:

55790

AN XY:

510632

show subpopulations

Gnomad4 AFR exome

AF:

0.0810

Gnomad4 AMR exome

AF:

0.0687

Gnomad4 ASJ exome

AF:

0.0658

Gnomad4 EAS exome

AF:

0.0509

Gnomad4 SAS exome

AF:

0.109

Gnomad4 FIN exome

AF:

0.0669

Gnomad4 NFE exome

AF:

0.119

Gnomad4 OTH exome

AF:

0.104

GnomAD4 genome

AF:

0.0749

AC:

10378

AN:

138492

Hom.:

398

Cov.:

AF XY:

0.0746

AC XY:

5009

AN XY:

67102

show subpopulations

Gnomad4 AFR

AF:

0.0468

Gnomad4 AMR

AF:

0.0785

Gnomad4 ASJ

AF:

0.0525

Gnomad4 EAS

AF:

0.0397

Gnomad4 SAS

AF:

0.0977

Gnomad4 FIN

AF:

0.0666

Gnomad4 NFE

AF:

0.0931

Gnomad4 OTH

AF:

0.0756

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 09, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

11092-12_11092-11delTT in intron 79 of RYR2: This variant is not expected to hav e clinical significance because it is located outside the conserved +/- 1, 2 reg ion of the splicing consensus sequence and as part of a polyT stretch. -

Feb 11, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Dec 10, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Aug 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over