rs143537474

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-237042215-C-T
• chr1-237042215-C-A
• chr1-237042215-C-G

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.-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
• 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 -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 VariationId 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.

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>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 105	NP_001026.2	Q92736-1
	RYR2	NM_001035.3	MANE Select	c.-307C>T		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>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.-307C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.-307C>T		5_prime_UTR	Exon 1 of 105	ENSP00000355533.2	Q92736-1

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

African (AFR) AF: 0.344 AC: 121 AN: 352

American (AMR) AF: 0.0544 AC: 21 AN: 386

Ashkenazi Jewish (ASJ) AF: 0.00267 AC: 1 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: 0.0303 AC: 2 AN: 66

European-Non Finnish (NFE) AF: 0.00269 AC: 24 AN: 8914

Other (OTH) AF: 0.0207 AC: 17 AN: 820

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

African (AFR) AF: 0.324 AC: 13416 AN: 41406

American (AMR) AF: 0.0432 AC: 660 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: 0.00166 AC: 8 AN: 4824

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

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.00246 AC: 167 AN: 67832

Other (OTH) AF: 0.0683 AC: 144 AN: 2108

Alfa AF: 0.00207 Hom.: 4

Bravo AF: 0.110

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.4
DANN	Benign	0.87
PhyloP100		-1.8
PromoterAI		0.054	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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;