rs138630815

chr19-38440793-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS1

The NM_000540.3(RYR1):c.94C>T(p.Leu32Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,609,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 1.18

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 -6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000540.3
• PP2: Missense variant where missense usually causes diseases, RYR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.017810881).
• BP6: Variant 19-38440793-C-T is Benign according to our data. Variant chr19-38440793-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195083.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00115 (175/152268) while in subpopulation AFR AF= 0.00395 (164/41544). AF 95% confidence interval is 0.00345. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.94C>T	p.Leu32Phe	missense_variant	2/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.94C>T	p.Leu32Phe	missense_variant	2/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.94C>T	p.Leu32Phe	missense_variant	2/105	1		P4
RYR1	ENST00000599547.6	c.94C>T	p.Leu32Phe	missense_variant, NMD_transcript_variant	2/80	2

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000248 AC: 59 AN: 237566 Hom.: 0 AF XY: 0.000216 AC XY: 28 AN XY: 129710

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.000829

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000283

Gnomad OTH exome AF: 0.000346

GnomAD4 exome AF: 0.000137 AC: 199 AN: 1456906 Hom.: 1 Cov.: 31 AF XY: 0.000101 AC XY: 73 AN XY: 724536

Gnomad4 AFR exome AF: 0.00452

Gnomad4 AMR exome AF: 0.0000906

Gnomad4 ASJ exome AF: 0.000732

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74460

Gnomad4 AFR AF: 0.00395

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.00116

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000273 AC: 33

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 21, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	- -

RYR1-related disorder Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 16, 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). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.071	T;T
Polyphen		0.99	D;D
Vest4		0.36
MVP		0.94
MPC		0.95
ClinPred		0.033	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.30

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: rs138630815; hg19: chr19-38931433;