1-237042459-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001035.3(RYR2):c.-63G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,209,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: RYR2 NM_001035.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.215

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-237042459-G-T is Benign according to our data. Variant chr1-237042459-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296699.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00037 (56/151358) while in subpopulation SAS AF= 0.00352 (17/4826). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.-63G>T		5_prime_UTR_variant	1/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.-63G>T		5_prime_UTR_variant	1/105	1	NM_001035.3	P1
RYR2	ENST00000659194.3	c.-63G>T		5_prime_UTR_variant	1/105
RYR2	ENST00000660292.2	c.-63G>T		5_prime_UTR_variant	1/106
RYR2	ENST00000609119.2	c.-63G>T		5_prime_UTR_variant, NMD_transcript_variant	1/104	5

Frequencies

GnomAD3 genomes AF: 0.000370 AC: 56 AN: 151252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000383

Gnomad OTH AF: 0.00145

GnomAD4 exome AF: 0.000303 AC: 321 AN: 1058416 Hom.: 0 Cov.: 25 AF XY: 0.000336 AC XY: 168 AN XY: 500250

Gnomad4 AFR exome AF: 0.0000456

Gnomad4 AMR exome AF: 0.000127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00516

Gnomad4 FIN exome AF: 0.000179

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.000526

GnomAD4 genome AF: 0.000370 AC: 56 AN: 151358 Hom.: 0 Cov.: 33 AF XY: 0.000405 AC XY: 30 AN XY: 74000

Gnomad4 AFR AF: 0.0000729

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.000384

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000529 Hom.: 0

Bravo AF: 0.000325

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK:

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Benign

15

Dann

Benign

0.84

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

Other links and lift over

dbSNP: rs578020342; hg19: chr1-237205759;