rs201032965

Variant names:

• chr19-38535956-G-A
• rs201032965
• NM_000540.3:c.11517-41G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38535956-G-A
• chr19-38535956-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000540.3(RYR1):​c.11517-41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,585,850 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.503
• 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

ENSG00000268055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-38535956-G-A is Benign according to our data. Variant chr19-38535956-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 256407.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000985 (150/152282) while in subpopulation AFR AF = 0.00332 (138/41540). AF 95% confidence interval is 0.00287. There are 0 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.11517-41G>A		intron_variant	Intron 81 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.11517-41G>A		intron_variant	Intron 81 of 105	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000249 AC: 58 AN: 233100 AF XY: 0.000184

Gnomad AFR exome AF: 0.00324

Gnomad AMR exome AF: 0.000215

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000109 AC: 156 AN: 1433568 Hom.: 1 Cov.: 28 AF XY: 0.0000799 AC XY: 57 AN XY: 712980

African (AFR) AF: 0.00402 AC: 133 AN: 33088

American (AMR) AF: 0.000163 AC: 7 AN: 43066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 39408

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52752

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5728

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090988

Other (OTH) AF: 0.000202 AC: 12 AN: 59494

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152282 Hom.: 0 Cov.: 31 AF XY: 0.000940 AC XY: 70 AN XY: 74466

African (AFR) AF: 0.00332 AC: 138 AN: 41540

American (AMR) AF: 0.000719 AC: 11 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.00122

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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	-0.82
CADD	Benign	1.1
DANN	Benign	0.66
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism

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: rs201032965; hg19: chr19-39026596;