rs138156449

chr19-38578002-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

The NM_000540.3(RYR1):c.14257G>A(p.Ala4753Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,614,084 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. A4753V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (1 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.14

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 -2 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 117) in uniprot entity RYR1_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in NM_000540.3
• PP2: Missense variant where missense usually causes diseases, RYR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.010935962).
• BP6: Variant 19-38578002-G-A is Benign according to our data. Variant chr19-38578002-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.14257G>A	p.Ala4753Thr	missense_variant	98/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.14257G>A	p.Ala4753Thr	missense_variant	98/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 251304 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135866

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461886 Hom.: 1 Cov.: 32 AF XY: 0.0000646 AC XY: 47 AN XY: 727246

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.000179

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: 0.0000993

GnomAD4 genome AF: 0.000756 AC: 115 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74418

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000368 Hom.: 0

Bravo AF: 0.000722

ExAC AF: 0.000272 AC: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22473935, 20681998) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 04, 2022	- -

RYR1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

RYR1-Related Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	21
Dann	Benign	0.95
Eigen	Benign	-0.074
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.044	D
MutationTaster	Benign	0.83	N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.38	T;T
Polyphen		0.40	B;B
Vest4		0.32
MVP		0.97
MPC		0.55
ClinPred		0.034	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.45

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: rs138156449; hg19: chr19-39068642;