chr1-237548344-T-C

Variant names:

• chr1-237548344-T-C
• rs2618661
• NM_001035.3:c.2907-87T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.2907-87T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.938 in 1,393,984 control chromosomes in the GnomAD database, including 617,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (57878 hom., cov: 32)
  • Exomes 𝑓: 0.95 (559708 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.220
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-237548344-T-C is Benign according to our data. Variant chr1-237548344-T-C is described in ClinVar as Benign. ClinVar VariationId is 671749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.2907-87T>C		intron_variant	Intron 25 of 104	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.2907-87T>C		intron_variant	Intron 25 of 104	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.2907-87T>C		intron_variant	Intron 25 of 105			ENSP00000499393.2
RYR2	ENST00000609119.2	n.2907-87T>C		intron_variant	Intron 25 of 103	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130456 AN: 152084 Hom.: 57852 Cov.: 32

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.931

Gnomad ASJ AF: 0.965

Gnomad EAS AF: 0.888

Gnomad SAS AF: 0.962

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.958

Gnomad OTH AF: 0.885

GnomAD4 exome AF: 0.948 AC: 1176738 AN: 1241784 Hom.: 559708 AF XY: 0.949 AC XY: 583517 AN XY: 614856

African (AFR) AF: 0.594 AC: 17157 AN: 28878

American (AMR) AF: 0.951 AC: 31695 AN: 33340

Ashkenazi Jewish (ASJ) AF: 0.960 AC: 20914 AN: 21792

East Asian (EAS) AF: 0.885 AC: 31462 AN: 35532

South Asian (SAS) AF: 0.968 AC: 67742 AN: 69996

European-Finnish (FIN) AF: 0.972 AC: 46735 AN: 48104

Middle Eastern (MID) AF: 0.901 AC: 4136 AN: 4592

European-Non Finnish (NFE) AF: 0.959 AC: 907921 AN: 947004

Other (OTH) AF: 0.932 AC: 48976 AN: 52546

GnomAD4 genome AF: 0.858 AC: 130526 AN: 152200 Hom.: 57878 Cov.: 32 AF XY: 0.861 AC XY: 64064 AN XY: 74428

African (AFR) AF: 0.606 AC: 25138 AN: 41460

American (AMR) AF: 0.931 AC: 14228 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.965 AC: 3351 AN: 3472

East Asian (EAS) AF: 0.889 AC: 4608 AN: 5186

South Asian (SAS) AF: 0.962 AC: 4641 AN: 4824

European-Finnish (FIN) AF: 0.976 AC: 10366 AN: 10616

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.958 AC: 65195 AN: 68036

Other (OTH) AF: 0.884 AC: 1868 AN: 2112

Alfa AF: 0.902 Hom.: 10644

Bravo AF: 0.842

Asia WGS AF: 0.913 AC: 3173 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

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	-0.86
CADD	Benign	2.4
DANN	Benign	0.46
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2618661; hg19: chr1-237711644;