NM_001035.3:c.1612+14T>C

Variant names:

• chr1-237456749-T-C
• rs2045955
• NM_001035.3:c.1612+14T>C

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.1612+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,611,822 control chromosomes in the GnomAD database, including 249,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19675 hom., cov: 30)
  • Exomes 𝑓: 0.56 (229974 hom.)
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.669
• Publications: 16 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=-0.85).
• BP6: Variant 1-237456749-T-C is Benign according to our data. Variant chr1-237456749-T-C is described in ClinVar as Benign. ClinVar VariationId is 43752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 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.1612+14T>C		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.1612+14T>C		intron	N/A	ENSP00000355533.2	Q92736-1
	RYR2	ENST00000661330.2		c.1612+14T>C		intron	N/A	ENSP00000499393.2	A0A590UJF6
	RYR2	ENST00000609119.2	TSL:5	n.1612+14T>C		intron	N/A	ENSP00000499659.2	A0A590UK06

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74754 AN: 151754 Hom.: 19676 Cov.: 30

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.567

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.496

GnomAD2 exomes AF: 0.557 AC: 138103 AN: 247766 AF XY: 0.559

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.587

Gnomad ASJ exome AF: 0.549

Gnomad EAS exome AF: 0.792

Gnomad FIN exome AF: 0.570

Gnomad NFE exome AF: 0.546

Gnomad OTH exome AF: 0.552

GnomAD4 exome AF: 0.557 AC: 813826 AN: 1459950 Hom.: 229974 Cov.: 37 AF XY: 0.557 AC XY: 404538 AN XY: 726272

African (AFR) AF: 0.297 AC: 9923 AN: 33438

American (AMR) AF: 0.574 AC: 25621 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 14560 AN: 26070

East Asian (EAS) AF: 0.826 AC: 32772 AN: 39676

South Asian (SAS) AF: 0.550 AC: 47385 AN: 86130

European-Finnish (FIN) AF: 0.569 AC: 30283 AN: 53192

Middle Eastern (MID) AF: 0.479 AC: 2758 AN: 5756

European-Non Finnish (NFE) AF: 0.556 AC: 617189 AN: 1110758

Other (OTH) AF: 0.553 AC: 33335 AN: 60310

GnomAD4 genome AF: 0.492 AC: 74777 AN: 151872 Hom.: 19675 Cov.: 30 AF XY: 0.498 AC XY: 36965 AN XY: 74208

African (AFR) AF: 0.307 AC: 12728 AN: 41410

American (AMR) AF: 0.536 AC: 8169 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1920 AN: 3470

East Asian (EAS) AF: 0.802 AC: 4128 AN: 5148

South Asian (SAS) AF: 0.566 AC: 2728 AN: 4816

European-Finnish (FIN) AF: 0.575 AC: 6057 AN: 10530

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37296 AN: 67946

Other (OTH) AF: 0.496 AC: 1046 AN: 2110

Alfa AF: 0.523 Hom.: 60404

Bravo AF: 0.480

Asia WGS AF: 0.647 AC: 2250 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Catecholaminergic polymorphic ventricular tachycardia 1 (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 2 (2)
-	-	2	not provided (2)
-	-	1	Cardiac arrhythmia (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.13
DANN	Benign	0.56
PhyloP100		-0.67
Mutation Taster		=100/0	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: rs2045955; hg19: chr1-237620049;