NM_001035.3:c.14091-10G>T

Variant names:

• chr1-237801846-G-T
• rs199569629
• NM_001035.3:c.14091-10G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001035.3(RYR2):​c.14091-10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 intron
• Scores: Splicing: ADA: 0.00004461
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0720
• 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: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-237801846-G-T is Benign according to our data. Variant chr1-237801846-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 463574.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.14091-10G>T		intron	N/A	NP_001026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.14091-10G>T		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.14109-10G>T		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*5183-10G>T		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.000337 AC: 44 AN: 130532 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00262

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000215

Gnomad OTH AF: 0.000564

GnomAD2 exomes AF: 0.00608 AC: 1122 AN: 184540 AF XY: 0.00609

Gnomad AFR exome AF: 0.00317

Gnomad AMR exome AF: 0.00623

Gnomad ASJ exome AF: 0.00535

Gnomad EAS exome AF: 0.00448

Gnomad FIN exome AF: 0.00469

Gnomad NFE exome AF: 0.00479

Gnomad OTH exome AF: 0.00802

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00147 AC: 1872 AN: 1271770 Hom.: 0 Cov.: 26 AF XY: 0.00159 AC XY: 1005 AN XY: 630910

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00428 AC: 120 AN: 28030

American (AMR) AF: 0.0123 AC: 411 AN: 33306

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 58 AN: 22354

East Asian (EAS) AF: 0.000275 AC: 10 AN: 36320

South Asian (SAS) AF: 0.00647 AC: 428 AN: 66130

European-Finnish (FIN) AF: 0.00285 AC: 119 AN: 41750

Middle Eastern (MID) AF: 0.00266 AC: 13 AN: 4890

European-Non Finnish (NFE) AF: 0.000642 AC: 633 AN: 986588

Other (OTH) AF: 0.00153 AC: 80 AN: 52402

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000337 AC: 44 AN: 130532 Hom.: 0 Cov.: 32 AF XY: 0.000429 AC XY: 27 AN XY: 62956

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000203 AC: 7 AN: 34564

American (AMR) AF: 0.000151 AC: 2 AN: 13286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3128

East Asian (EAS) AF: 0.00 AC: 0 AN: 4276

South Asian (SAS) AF: 0.00 AC: 0 AN: 3830

European-Finnish (FIN) AF: 0.00262 AC: 21 AN: 8012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000215 AC: 13 AN: 60550

Other (OTH) AF: 0.000564 AC: 1 AN: 1774

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00255 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.55
PhyloP100		-0.072

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0020
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: rs199569629; hg19: chr1-237965146;