rs755065800

Positions:

• chr19-38565203-C-T

Variant summary

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

The NM_000540.3(RYR1):​c.12869C>T​(p.Ala4290Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000676 in 1,005,642 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.397

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0445036).
• BP6: Variant 19-38565203-C-T is Benign according to our data. Variant chr19-38565203-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544505.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr19-38565203-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00271 (397/146552) while in subpopulation AFR AF= 0.00909 (372/40902). AF 95% confidence interval is 0.00833. There are 1 homozygotes in gnomad4. There are 198 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12869C>T	p.Ala4290Val	missense_variant	91/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12869C>T	p.Ala4290Val	missense_variant	91/106	5	NM_000540.3	ENSP00000352608	A2

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 396 AN: 146446 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000814

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000759

Gnomad OTH AF: 0.00199

GnomAD4 exome AF: 0.000329 AC: 283 AN: 859090 Hom.: 2 Cov.: 30 AF XY: 0.000338 AC XY: 135 AN XY: 399468

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000913

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000744

Gnomad4 OTH exome AF: 0.000939

GnomAD4 genome AF: 0.00271 AC: 397 AN: 146552 Hom.: 1 Cov.: 32 AF XY: 0.00277 AC XY: 198 AN XY: 71354

Gnomad4 AFR AF: 0.00909

Gnomad4 AMR AF: 0.000813

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000759

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.00214 Hom.: 0

ExAC AF: 0.00255 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

RYR1-related disorder Benign:2

Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 06, 2023	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). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.31	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.26	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.045	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.69	.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.27
Sift	Benign	0.62	T;T
Polyphen		0.39	B;B
Vest4		0.15
MutPred		0.33		.;Gain of MoRF binding (P = 0.0714);
MVP		0.82
MPC		0.73
ClinPred		0.070	T
GERP RS		-2.3
Varity_R		0.072
gMVP		0.32

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: rs755065800; hg19: chr19-39055843;