dbSNP rs189170845: RYR1:c.6549-45C>T (chr19-38496170-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000540.3(RYR1):c.6549-45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,543,930 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00085 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 9 hom. )

Consequence

RYR1
NM_000540.3 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.982

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 19-38496170-C-T is Benign according to our data. Variant chr19-38496170-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256536.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.6549-45C>T		intron_variant	Intron 39 of 105	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.6549-45C>T	intron_variant	Intron 39 of 105	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.6549-45C>T	intron_variant	Intron 39 of 104	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 link	n.6549-45C>T	intron_variant	Intron 39 of 79	2		ENSP00000471601.2	M0R127
RYR1	ENST00000594335.5 link	n.-46C>T	upstream_gene_variant		1		ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes

AF:

0.000854

AC:

130

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00170

AC:

417

AN:

245694

Hom.:

AF XY:

0.00170

AC XY:

227

AN XY:

133522

show subpopulations

Gnomad AFR exome

AF:

0.0000625

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.000273

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.000972

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.000908

AC:

1263

AN:

1391644

Hom.:

Cov.:

AF XY:

0.000957

AC XY:

666

AN XY:

696144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.0238

Gnomad4 EAS exome

AF:

0.000229

Gnomad4 SAS exome

AF:

0.000153

Gnomad4 FIN exome

AF:

0.00168

Gnomad4 NFE exome

AF:

0.000325

Gnomad4 OTH exome

AF:

0.00344

GnomAD4 genome

AF:

0.000854

AC:

130

AN:

152286

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00449

Hom.:

Bravo

AF:

0.000979

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.089

DANN

Benign

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over