rs202015519

chr1-237548459-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001035.3(RYR2):c.2935G>T(p.Ala979Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,613,942 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A979V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000096 (3 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 4.74

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.05739823).
• BP6: Variant 1-237548459-G-T is Benign according to our data. Variant chr1-237548459-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178118.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=1}. Variant chr1-237548459-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000571 (87/152294) while in subpopulation AFR AF= 0.00204 (85/41574). AF 95% confidence interval is 0.00169. There are 1 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.2935G>T	p.Ala979Ser	missense_variant	26/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.2935G>T	p.Ala979Ser	missense_variant	26/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.2935G>T	p.Ala979Ser	missense_variant	26/106
RYR2	ENST00000659194.3	c.2935G>T	p.Ala979Ser	missense_variant	26/105
RYR2	ENST00000609119.2	c.2935G>T	p.Ala979Ser	missense_variant, NMD_transcript_variant	26/104	5

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000141 AC: 35 AN: 249060 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135116

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461648 Hom.: 3 Cov.: 30 AF XY: 0.0000866 AC XY: 63 AN XY: 727094

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74468

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000431 Hom.: 0

Bravo AF: 0.000684

ESP6500AA AF: 0.00237 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2021	Variant summary: RYR2 c.2935G>T (p.Ala979Ser) results in a conservative amino acid change located in the Ryanodine receptor Ryr domain (IPR003032) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 249060 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2935G>T has been reported in the literature in patients (Lopes_2015, Torkamani_2016, Landstrom_2017), however these data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, where five has classified the variant as benign/likely benign and two have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 01, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 17, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 18, 2023

See Variant Classification Assertion Criteria. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.057	T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.56
Sift	Benign	0.032	D;.
Polyphen		0.81	P;.
Vest4		0.30
MVP		0.75
MPC		0.76
ClinPred		0.031	T
GERP RS		5.8
Varity_R		0.27
gMVP		0.50

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: rs202015519; hg19: chr1-237711759;