NM_001035.3:c.10699C>A

Variant names:

• chr1-237726282-C-A
• NM_001035.3:c.10699C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001035.3(RYR2):​c.10699C>A​(p.Arg3567Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3567C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0580

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08635557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.10699C>A	p.Arg3567Ser	missense_variant	Exon 75 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.10699C>A	p.Arg3567Ser	missense_variant	Exon 75 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.1	c.505C>A	p.Arg169Ser	missense_variant	Exon 6 of 12			ENSP00000499393.2
RYR2	ENST00000609119.2	n.*1734C>A		non_coding_transcript_exon_variant	Exon 73 of 104	5		ENSP00000499659.2
RYR2	ENST00000609119.2	n.*1734C>A		3_prime_UTR_variant	Exon 73 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433044 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 711554

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: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	5.1
DANN	Benign	0.23
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.59	T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.49	N;.
REVEL	Benign	0.25
Sift	Benign	0.48	T;.
Polyphen		0.0	B;.
Vest4		0.071
MutPred		0.37		Loss of MoRF binding (P = 0.0149);.;
MVP		0.45
MPC		0.41
ClinPred		0.023	T
GERP RS		-7.2
Varity_R		0.097
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-237889582;