1-237042215-C-G

Variant names:

• chr1-237042215-C-G
• rs143537474
• NM_001035.3:c.-307C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001035.3(RYR2):​c.-307C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 164,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: RYR2 NM_001035.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78
• Publications: 0 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: ClinGen, G2P, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000244 (37/151792) while in subpopulation SAS AF = 0.000622 (3/4824). AF 95% confidence interval is 0.000293. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 37 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.-307C>G		5_prime_UTR	Exon 1 of 105	NP_001026.2	Q92736-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.-307C>G		5_prime_UTR	Exon 1 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.-307C>G		5_prime_UTR	Exon 1 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.-307C>G		non_coding_transcript_exon	Exon 1 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.000251 AC: 38 AN: 151686 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000304 AC: 4 AN: 13166 Hom.: 0 Cov.: 0 AF XY: 0.000410 AC XY: 3 AN XY: 7314

African (AFR) AF: 0.00 AC: 0 AN: 352

American (AMR) AF: 0.00 AC: 0 AN: 386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 374

East Asian (EAS) AF: 0.00 AC: 0 AN: 520

South Asian (SAS) AF: 0.00 AC: 0 AN: 126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.000449 AC: 4 AN: 8914

Other (OTH) AF: 0.00 AC: 0 AN: 820

GnomAD4 genome AF: 0.000244 AC: 37 AN: 151792 Hom.: 0 Cov.: 32 AF XY: 0.000216 AC XY: 16 AN XY: 74206

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000413 AC: 28 AN: 67834

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.7
DANN	Benign	0.55
PhyloP100		-1.8
PromoterAI		0.061	Neutral

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: rs143537474; hg19: chr1-237205515;