chr19-38564963-A-T

Variant names:

• chr19-38564963-A-T
• rs138932463
• NM_000540.3:c.12629A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000540.3(RYR1):​c.12629A>T​(p.Lys4210Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,430,282 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K4210R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000540.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12629A>T	p.Lys4210Met	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.12629A>T	p.Lys4210Met	missense_variant	Exon 91 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430282 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708578

⚠️ 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: 32940

American (AMR) AF: 0.00 AC: 0 AN: 40228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25338

East Asian (EAS) AF: 0.00 AC: 0 AN: 38458

South Asian (SAS) AF: 0.00 AC: 0 AN: 81544

European-Finnish (FIN) AF: 0.0000201 AC: 1 AN: 49698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097298

Other (OTH) AF: 0.00 AC: 0 AN: 59220

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Benign	0.89
DEOGEN2	Pathogenic	0.85	.;D
Eigen	Benign	0.11
Eigen_PC	Benign	0.0067
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.5	.;M
PhyloP100		5.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D
Polyphen		0.95	P;P
Vest4		0.50
MutPred		0.40		.;Loss of methylation at K4210 (P = 0.0075);
MVP		1.0
MPC		0.79
ClinPred		0.98	D
GERP RS		2.0
PromoterAI		0.011	Neutral
Varity_R		0.53
gMVP		0.89
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs138932463; hg19: chr19-39055603;