rs760285455

chr19-38455535-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP2 PP3_Moderate

The NM_000540.3(RYR1):c.1661A>G(p.Glu554Gly) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E554D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

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 Uncertain_significance. Variant got 5 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, 5 uncertain in NM_000540.3
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.1661A>G	p.Glu554Gly	missense_variant	15/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.1661A>G	p.Glu554Gly	missense_variant	15/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.1661A>G	p.Glu554Gly	missense_variant	15/105	1		P4
RYR1	ENST00000599547.6	c.1661A>G	p.Glu554Gly	missense_variant, NMD_transcript_variant	15/80	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000818 AC: 20 AN: 244404 Hom.: 0 AF XY: 0.0000755 AC XY: 10 AN XY: 132420

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000150

Gnomad NFE exome AF: 0.0000991

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000686 AC: 10 AN: 1457712 Hom.: 0 Cov.: 54 AF XY: 0.00000690 AC XY: 5 AN XY: 725044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000767

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 31

Alfa AF: 0.000415 Hom.: 0

ExAC AF: 0.000544 AC: 66

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jul 01, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Benign	0.20	N
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.017	D;D
Polyphen		1.0	D;D
Vest4		0.58
MVP		1.0
MPC		1.1
ClinPred		0.88	D
GERP RS		4.0
Varity_R		0.57
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs760285455; hg19: chr19-38946175; COSMIC: COSV62091886;