1-237042215-C-T

Position:

• chr1-237042215-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001035.3(RYR2):​c.-307C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 164,936 control chromosomes in the GnomAD database, including 2,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (2287 hom., cov: 32)
  • Exomes 𝑓: 0.014 (32 hom.)
• Consequence: RYR2 NM_001035.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.78

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-237042215-C-T is Benign according to our data. Variant chr1-237042215-C-T is described in ClinVar as [Benign]. Clinvar id is 1269966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.-307C>T		5_prime_UTR_premature_start_codon_gain_variant	1/105	ENST00000366574.7	NP_001026.2
RYR2	NM_001035.3	c.-307C>T		5_prime_UTR_variant	1/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574	c.-307C>T		5_prime_UTR_premature_start_codon_gain_variant	1/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000366574	c.-307C>T		5_prime_UTR_variant	1/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.-307C>T		5_prime_UTR_premature_start_codon_gain_variant	1/104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.-307C>T		non_coding_transcript_exon_variant	1/104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.-307C>T		5_prime_UTR_variant	1/104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0948 AC: 14371 AN: 151664 Hom.: 2279 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.00246

Gnomad OTH AF: 0.0690

GnomAD4 exome AF: 0.0141 AC: 186 AN: 13166 Hom.: 32 Cov.: 0 AF XY: 0.0119 AC XY: 87 AN XY: 7314

Gnomad4 AFR exome AF: 0.344

Gnomad4 AMR exome AF: 0.0544

Gnomad4 ASJ exome AF: 0.00267

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00269

Gnomad4 OTH exome AF: 0.0207

GnomAD4 genome AF: 0.0949 AC: 14408 AN: 151770 Hom.: 2287 Cov.: 32 AF XY: 0.0921 AC XY: 6837 AN XY: 74200

Gnomad4 AFR AF: 0.324

Gnomad4 AMR AF: 0.0432

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00246

Gnomad4 OTH AF: 0.0683

Alfa AF: 0.00207 Hom.: 4

Bravo AF: 0.110

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.4
DANN	Benign	0.87

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: rs143537474; hg19: chr1-237205515;