1-237801833-ATTTTT-ATTTT

Variant names:

• chr1-237801833-AT-A
• rs35563566
• NM_001035.3:c.14091-11delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001035.3(RYR2):​c.14091-11delT variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 0)
  • Exomes 𝑓: 0.099 (1 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.362
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 1-237801833-AT-A is Benign according to our data. Variant chr1-237801833-AT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 43737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.14091-11delT		intron	N/A	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.14091-22delT		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.14109-22delT		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*5183-22delT		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 261 AN: 147836 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000786

Gnomad SAS AF: 0.000634

Gnomad FIN AF: 0.00568

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00347

GnomAD2 exomes AF: 0.130 AC: 21832 AN: 167748 AF XY: 0.130

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.0739

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.0993 AC: 111640 AN: 1124718 Hom.: 1 Cov.: 12 AF XY: 0.0998 AC XY: 56002 AN XY: 561062

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.106 AC: 2732 AN: 25832

American (AMR) AF: 0.145 AC: 5132 AN: 35348

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 1898 AN: 21006

East Asian (EAS) AF: 0.0545 AC: 1865 AN: 34196

South Asian (SAS) AF: 0.0974 AC: 6732 AN: 69130

European-Finnish (FIN) AF: 0.110 AC: 4067 AN: 36814

Middle Eastern (MID) AF: 0.0595 AC: 282 AN: 4736

European-Non Finnish (NFE) AF: 0.0992 AC: 84358 AN: 850356

Other (OTH) AF: 0.0967 AC: 4574 AN: 47300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00179 AC: 265 AN: 147904 Hom.: 0 Cov.: 0 AF XY: 0.00188 AC XY: 135 AN XY: 71976

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00260 AC: 105 AN: 40386

American (AMR) AF: 0.00122 AC: 18 AN: 14798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.000789 AC: 4 AN: 5068

South Asian (SAS) AF: 0.000635 AC: 3 AN: 4728

European-Finnish (FIN) AF: 0.00568 AC: 54 AN: 9506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00109 AC: 73 AN: 66772

Other (OTH) AF: 0.00393 AC: 8 AN: 2038

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0724 Hom.: 457

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 16, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

14091-11delT in intron 97 of RYR2: This variant is not expected to have clinical significance because it is located outside the conserved +/- 1, 2 region of the splicing consensus sequence and as part of a polyT stretch. This variant has b een reported in dbSNP (rs72027983 & rs55683196) without frequency information.

not provided Benign:1

Aug 30, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

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: rs35563566; hg19: chr1-237965133; COSMIC: COSV63698783;