rs146793133

chr19-38506525-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000540.3(RYR1):c.8671A>C(p.Lys2891Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,614,010 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K2891K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 9.27

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.09842819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.8671A>C	p.Lys2891Gln	missense_variant	56/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.8671A>C	p.Lys2891Gln	missense_variant	56/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.8671A>C	p.Lys2891Gln	missense_variant	56/105	1		P4
RYR1	ENST00000594335.5	c.2125A>C	p.Lys709Gln	missense_variant, NMD_transcript_variant	17/49	1
RYR1	ENST00000599547.6	c.8671A>C	p.Lys2891Gln	missense_variant, NMD_transcript_variant	56/80	2

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152064 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000152 AC: 38 AN: 250210 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135310

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461828 Hom.: 0 Cov.: 36 AF XY: 0.0000770 AC XY: 56 AN XY: 727208

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152182 Hom.: 0 Cov.: 31 AF XY: 0.000430 AC XY: 32 AN XY: 74396

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.000434

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2023	Reported as a secondary finding via exome sequencing in two patients reported to have either developmental delay or chronic constipation (Chetruengchai et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12668474, 34621001) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 13, 2023	- -

RYR1-related disorder Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 05, 2023	The RYR1 c.8671A>C variant is predicted to result in the amino acid substitution p.Lys2891Gln. This variant was observed in 2 individuals with RYR1 unrelated conditions and assessed as variant of unknown significance (Chetruengchai et al 2022. PubMed ID: 34621001 STable1). This variant is reported in 0.14% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38997165-A-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	25
Dann	Benign	0.85
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.033	D;D
Polyphen		0.99	D;D
Vest4		0.51
MVP		1.0
MPC		0.60
ClinPred		0.14	T
GERP RS		3.1
Varity_R		0.71
gMVP		0.72

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: rs146793133; hg19: chr19-38997165;