1-237456575-ATTTT-ATTTTTT

Variant names:

• chr1-237456575-A-ATT
• rs397516518
• NM_001035.3:c.1477-12_1477-11dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.1477-12_1477-11dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 0)
  • Exomes 𝑓: 0.0093 (2 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.43
• 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 -16 ACMG points.

• BP6: Variant 1-237456575-A-ATT is Benign according to our data. Variant chr1-237456575-A-ATT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1204240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.1477-12_1477-11dupTT		intron_variant	Intron 15 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.1477-25_1477-24insTT		intron_variant	Intron 15 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.1477-25_1477-24insTT		intron_variant	Intron 15 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.1477-25_1477-24insTT		intron_variant	Intron 15 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1585 AN: 149082 Hom.: 40 Cov.: 0

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.00521

Gnomad EAS AF: 0.0997

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.000832

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.0113

GnomAD2 exomes AF: 0.0142 AC: 2014 AN: 142038 AF XY: 0.0137

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.00960

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.0798

Gnomad FIN exome AF: 0.00623

Gnomad NFE exome AF: 0.00703

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00932 AC: 11267 AN: 1209390 Hom.: 2 Cov.: 0 AF XY: 0.00946 AC XY: 5585 AN XY: 590404

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

African (AFR) AF: 0.0197 AC: 513 AN: 25986

American (AMR) AF: 0.0104 AC: 258 AN: 24772

Ashkenazi Jewish (ASJ) AF: 0.00991 AC: 194 AN: 19576

East Asian (EAS) AF: 0.0690 AC: 2199 AN: 31888

South Asian (SAS) AF: 0.0221 AC: 1119 AN: 50622

European-Finnish (FIN) AF: 0.00602 AC: 227 AN: 37734

Middle Eastern (MID) AF: 0.0193 AC: 91 AN: 4706

European-Non Finnish (NFE) AF: 0.00617 AC: 5954 AN: 965192

Other (OTH) AF: 0.0146 AC: 712 AN: 48914

⚠️ 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: 0.0106 AC: 1583 AN: 149164 Hom.: 40 Cov.: 0 AF XY: 0.0116 AC XY: 841 AN XY: 72574

African (AFR) AF: 0.0171 AC: 699 AN: 40768

American (AMR) AF: 0.00607 AC: 91 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.00521 AC: 18 AN: 3456

East Asian (EAS) AF: 0.0996 AC: 502 AN: 5040

South Asian (SAS) AF: 0.0210 AC: 99 AN: 4716

European-Finnish (FIN) AF: 0.000832 AC: 8 AN: 9620

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.00206 AC: 139 AN: 67320

Other (OTH) AF: 0.0107 AC: 22 AN: 2062

Alfa AF: 0.000401 Hom.: 648

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Aug 06, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 16, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516518; hg19: chr1-237619875;