1-237042523-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_001035.3(RYR2):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR2 NM_001035.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.584

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.2T>C	p.Met1?	start_lost	1/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.2T>C	p.Met1?	start_lost	1/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.2T>C	p.Met1?	start_lost	1/106
RYR2	ENST00000659194.3	c.2T>C	p.Met1?	start_lost	1/105
RYR2	ENST00000609119.2	c.2T>C	p.Met1?	start_lost, NMD_transcript_variant	1/104	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 270562 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 137460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK:

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2022

Initiation codon variant in a gene for which loss of function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; No data available from control populations to assess the frequency of this variant -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

D

BayesDel_noAF

Pathogenic

0.14

Cadd

Benign

20

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.56

D

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.078

FATHMM_MKL

Benign

0.74

D

LIST_S2

Uncertain

0.90

D

M_CAP

Pathogenic

1.0

D

MetaRNN

Pathogenic

0.98

D

MetaSVM

Uncertain

0.41

D

MutationTaster

Benign

1.0

D

PROVEAN

Benign

-2.3

N

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D

Polyphen

0.0060

B

Vest4

0.59

MutPred

0.99

Gain of glycosylation at M1 (P = 0.0233);

MVP

0.96

ClinPred

0.68

D

GERP RS

3.1

Varity_R

0.82

gMVP

0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs1453040850; hg19: chr1-237205823;