1-237042458-G-GGCC

Variant names:

• chr1-237042458-G-GGCC
• rs794728699
• NM_001035.3:c.-50_-48dupCCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001035.3(RYR2):​c.-50_-48dupCCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,228,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: RYR2 NM_001035.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.215
• 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: Ambry Genetics, Laboratory for Molecular Medicine
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -10 ACMG points.

• BP6: Variant 1-237042458-G-GGCC is Benign according to our data. Variant chr1-237042458-G-GGCC is described in ClinVar as Benign. ClinVar VariationId is 201174.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00116 (176/151914) while in subpopulation AFR AF = 0.00354 (147/41536). AF 95% confidence interval is 0.00307. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 176 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.-50_-48dupCCG		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.-50_-48dupCCG		5_prime_UTR	Exon 1 of 105	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.-50_-48dupCCG		5_prime_UTR	Exon 1 of 106	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.-50_-48dupCCG		non_coding_transcript_exon	Exon 1 of 104	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 151806 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.000960

GnomAD4 exome AF: 0.000133 AC: 143 AN: 1076186 Hom.: 0 Cov.: 25 AF XY: 0.000157 AC XY: 80 AN XY: 508380

African (AFR) AF: 0.00300 AC: 67 AN: 22332

American (AMR) AF: 0.000497 AC: 4 AN: 8050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13760

East Asian (EAS) AF: 0.0000388 AC: 1 AN: 25746

South Asian (SAS) AF: 0.0000518 AC: 1 AN: 19294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34398

Middle Eastern (MID) AF: 0.000601 AC: 2 AN: 3328

European-Non Finnish (NFE) AF: 0.0000585 AC: 53 AN: 906578

Other (OTH) AF: 0.000351 AC: 15 AN: 42700

GnomAD4 genome AF: 0.00116 AC: 176 AN: 151914 Hom.: 0 Cov.: 33 AF XY: 0.00120 AC XY: 89 AN XY: 74266

African (AFR) AF: 0.00354 AC: 147 AN: 41536

American (AMR) AF: 0.00124 AC: 19 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67882

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=299/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794728699; hg19: chr1-237205758;