rs77216903

chr19-38505359-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):c.8361C>T(p.Thr2787=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,612,366 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (6 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.35

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 19-38505359-C-T is Benign according to our data. Variant chr19-38505359-C-T is described in ClinVar as [Benign]. Clinvar id is 256574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38505359-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0045 (686/152288) while in subpopulation AFR AF= 0.0152 (631/41530). AF 95% confidence interval is 0.0142. There are 7 homozygotes in gnomad4. There are 334 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.8361C>T	p.Thr2787=	synonymous_variant	53/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.8361C>T	p.Thr2787=	synonymous_variant	53/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.8361C>T	p.Thr2787=	synonymous_variant	53/105	1		P4
RYR1	ENST00000594335.5	c.1815C>T	p.Thr605=	synonymous_variant, NMD_transcript_variant	14/49	1
RYR1	ENST00000599547.6	c.8361C>T	p.Thr2787=	synonymous_variant, NMD_transcript_variant	53/80	2

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 684 AN: 152170 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00116 AC: 289 AN: 248934 Hom.: 4 AF XY: 0.000862 AC XY: 116 AN XY: 134556

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.000804

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000469 AC: 685 AN: 1460078 Hom.: 6 Cov.: 33 AF XY: 0.000419 AC XY: 304 AN XY: 726206

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.000614

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00450 AC: 686 AN: 152288 Hom.: 7 Cov.: 32 AF XY: 0.00449 AC XY: 334 AN XY: 74462

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00210 Hom.: 0

Bravo AF: 0.00520

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RYR1: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2017

- -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Malignant hyperthermia, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	2.5
Dann	Benign	0.65

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: rs77216903; hg19: chr19-38995999;