chr1-237742271-T-C

Variant names:

• chr1-237742271-T-C
• rs3753630
• NM_001035.3:c.11092-25T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001035.3(RYR2):​c.11092-25T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 26)
  • Exomes 𝑓: 0.28 (32 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0580
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-237742271-T-C is Benign according to our data. Variant chr1-237742271-T-C is described in ClinVar as Benign. ClinVar VariationId is 257197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	NM_001035.3	MANE Select	c.11092-25T>C		intron	N/A	NP_001026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR2	ENST00000366574.7	TSL:1 MANE Select	c.11092-25T>C		intron	N/A	ENSP00000355533.2
	RYR2	ENST00000661330.2		c.11092-25T>C		intron	N/A	ENSP00000499393.2
	RYR2	ENST00000609119.2	TSL:5	n.*2127-25T>C		intron	N/A	ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 158 AN: 88202 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000451

Gnomad ASJ AF: 0.00192

Gnomad EAS AF: 0.000288

Gnomad SAS AF: 0.000822

Gnomad FIN AF: 0.00495

Gnomad MID AF: 0.00505

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.000816

GnomAD2 exomes AF: 0.0884 AC: 6209 AN: 70234 AF XY: 0.0898

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0827

Gnomad EAS exome AF: 0.0697

Gnomad FIN exome AF: 0.0866

Gnomad NFE exome AF: 0.0971

Gnomad OTH exome AF: 0.0998

GnomAD4 exome AF: 0.282 AC: 64636 AN: 229308 Hom.: 32 Cov.: 0 AF XY: 0.282 AC XY: 31956 AN XY: 113430

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

African (AFR) AF: 0.112 AC: 249 AN: 2216

American (AMR) AF: 0.347 AC: 1231 AN: 3544

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1140 AN: 3506

East Asian (EAS) AF: 0.327 AC: 1132 AN: 3464

South Asian (SAS) AF: 0.283 AC: 3514 AN: 12426

European-Finnish (FIN) AF: 0.282 AC: 1652 AN: 5850

Middle Eastern (MID) AF: 0.209 AC: 145 AN: 694

European-Non Finnish (NFE) AF: 0.281 AC: 53082 AN: 188972

Other (OTH) AF: 0.288 AC: 2491 AN: 8636

⚠️ 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: 0.00179 AC: 158 AN: 88210 Hom.: 0 Cov.: 26 AF XY: 0.00206 AC XY: 89 AN XY: 43294

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

African (AFR) AF: 0.00154 AC: 44 AN: 28548

American (AMR) AF: 0.000451 AC: 4 AN: 8876

Ashkenazi Jewish (ASJ) AF: 0.00192 AC: 4 AN: 2084

East Asian (EAS) AF: 0.000288 AC: 1 AN: 3468

South Asian (SAS) AF: 0.000829 AC: 2 AN: 2412

European-Finnish (FIN) AF: 0.00495 AC: 27 AN: 5450

Middle Eastern (MID) AF: 0.00526 AC: 1 AN: 190

European-Non Finnish (NFE) AF: 0.00209 AC: 74 AN: 35436

Other (OTH) AF: 0.000809 AC: 1 AN: 1236

⚠️ 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: 0.0674 Hom.: 179

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.38
PhyloP100		-0.058
Mutation Taster		=100/0	polymorphism

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: rs3753630; hg19: chr1-237905571; COSMIC: COSV63657727;