rs367543056

Variant names:

• chr19-38490709-A-G
• rs367543056
• NM_000540.3:c.6104A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-38490709-A-G
• chr19-38490709-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000540.3(RYR1):​c.6104A>G​(p.His2035Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H2035L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.6104A>G	p.His2035Arg	missense_variant	Exon 37 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6104A>G	p.His2035Arg	missense_variant	Exon 37 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.6104A>G	p.His2035Arg	missense_variant	Exon 37 of 105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.6104A>G		non_coding_transcript_exon_variant	Exon 37 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D
Polyphen		0.99	D;P
Vest4		0.70
MutPred		0.60		Loss of catalytic residue at D2037 (P = 0.2124);Loss of catalytic residue at D2037 (P = 0.2124);
MVP		0.95
MPC		0.57
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.82
gMVP		0.87
Mutation Taster		=0/100	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

Publications

LitVar

Other links and lift over

dbSNP: rs367543056; hg19: chr19-38981349;