rs2229142

chr19-38502907-C-Gchr19-38502907-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000540.3(RYR1):c.7863C>G(p.His2621Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2621Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.284

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000540.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3768224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.7863C>G	p.His2621Gln	missense_variant	49/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.7863C>G	p.His2621Gln	missense_variant	49/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.7863C>G	p.His2621Gln	missense_variant	49/105	1		P4
RYR1	ENST00000594335.5	c.1317C>G	p.His439Gln	missense_variant, NMD_transcript_variant	10/49	1
RYR1	ENST00000599547.6	c.7863C>G	p.His2621Gln	missense_variant, NMD_transcript_variant	49/80	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459128 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 725960

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function. This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2621 of the RYR1 protein (p.His2621Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	19
Dann	Benign	0.92
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.53	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.29	N;N
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.40
Sift	Benign	0.47	T;T
Polyphen		0.046	B;B
Vest4		0.74
MutPred		0.30		Loss of catalytic residue at L2623 (P = 0.1369);Loss of catalytic residue at L2623 (P = 0.1369);
MVP		0.93
MPC		0.34
ClinPred		0.62	D
GERP RS		3.0
Varity_R		0.33
gMVP		0.67

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: rs2229142; hg19: chr19-38993547;