19-38565524-C-T

Variant names:

• chr19-38565524-C-T
• rs1057520588
• NM_000540.3:c.13190C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000540.3(RYR1):​c.13190C>T​(p.Ala4397Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,350,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4397G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• Publications: 0 publications found

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]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• RYR1-related myopathy

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25148898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.13190C>T	p.Ala4397Val	missense_variant	Exon 91 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.13190C>T	p.Ala4397Val	missense_variant	Exon 91 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1350792 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 666062

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27622

American (AMR) AF: 0.00 AC: 0 AN: 32654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24078

East Asian (EAS) AF: 0.00 AC: 0 AN: 31616

South Asian (SAS) AF: 0.00 AC: 0 AN: 75818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 9.39e-7 AC: 1 AN: 1065362

Other (OTH) AF: 0.00 AC: 0 AN: 56348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Uncertain	0.64	.;D
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.69	T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.2	.;L
PhyloP100		1.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.19
Sift	Benign	0.14	T;T
Polyphen		0.0	B;B
Vest4		0.031
MutPred		0.37		.;Gain of solvent accessibility (P = 0.2291);
MVP		0.84
MPC		0.57
ClinPred		0.089	T
GERP RS		-0.11
PromoterAI		-0.031	Neutral
Varity_R		0.037
gMVP		0.20
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057520588; hg19: chr19-39056164;