chr1-237808889-A-G

Variant names:

• chr1-237808889-A-G
• rs41267519
• NM_001035.3:c.14299-12A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001035.3(RYR2):​c.14299-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00831 in 1,613,024 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (77 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Scores: Splicing: ADA: 0.0004738
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.472
• Publications: 2 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=-0.68).
• BP6: Variant 1-237808889-A-G is Benign according to our data. Variant chr1-237808889-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00652 (992/152232) while in subpopulation SAS AF = 0.0205 (99/4818). AF 95% confidence interval is 0.0173. There are 11 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 992 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.14299-12A>G		intron	N/A	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.14299-12A>G		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.14317-12A>G		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.*5391-12A>G		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 992 AN: 152114 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00847

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.00837 AC: 2085 AN: 249208 AF XY: 0.00940

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00504

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00497

Gnomad NFE exome AF: 0.00896

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00850 AC: 12413 AN: 1460792 Hom.: 77 Cov.: 30 AF XY: 0.00896 AC XY: 6514 AN XY: 726732

African (AFR) AF: 0.00146 AC: 49 AN: 33464

American (AMR) AF: 0.00521 AC: 233 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00211 AC: 55 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.0218 AC: 1880 AN: 86208

European-Finnish (FIN) AF: 0.00594 AC: 317 AN: 53358

Middle Eastern (MID) AF: 0.0200 AC: 115 AN: 5764

European-Non Finnish (NFE) AF: 0.00834 AC: 9267 AN: 1111206

Other (OTH) AF: 0.00822 AC: 496 AN: 60320

GnomAD4 genome AF: 0.00652 AC: 992 AN: 152232 Hom.: 11 Cov.: 33 AF XY: 0.00653 AC XY: 486 AN XY: 74432

African (AFR) AF: 0.00166 AC: 69 AN: 41524

American (AMR) AF: 0.00693 AC: 106 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4818

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10600

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00847 AC: 576 AN: 68032

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00729 Hom.: 4

Bravo AF: 0.00626

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	2	Catecholaminergic polymorphic ventricular tachycardia 1 (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 2 (1)
-	-	1	Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.33
DANN	Benign	0.54
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.024
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: rs41267519; hg19: chr1-237972189;