chr19-38565185-G-GCACGGCGGC

Variant names:

• chr19-38565185-G-GCACGGCGGC
• rs398123469
• NM_000540.3:c.12861_12869dupCACGGCGGC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_000540.3(RYR1):​c.12861_12869dupCACGGCGGC​(p.Ala4290_Ala4291insThrAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,117,934 control chromosomes in the GnomAD database, including 25 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0075 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (10 hom.)
• Consequence: RYR1 NM_000540.3 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.273

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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000540.3
• BP6: Variant 19-38565185-G-GCACGGCGGC is Benign according to our data. Variant chr19-38565185-G-GCACGGCGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93248.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00749 (1106/147610) while in subpopulation AFR AF= 0.0255 (1045/41038). AF 95% confidence interval is 0.0242. There are 15 homozygotes in gnomad4. There are 522 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12861_12869dupCACGGCGGC	p.Ala4290_Ala4291insThrAlaAla	disruptive_inframe_insertion	Exon 91 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12861_12869dupCACGGCGGC	p.Ala4290_Ala4291insThrAlaAla	disruptive_inframe_insertion	Exon 91 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.00745 AC: 1099 AN: 147504 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00297

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000603

Gnomad OTH AF: 0.00443

GnomAD4 exome AF: 0.000654 AC: 635 AN: 970324 Hom.: 10 Cov.: 29 AF XY: 0.000644 AC XY: 294 AN XY: 456650

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000619

Gnomad4 SAS exome AF: 0.000212

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000188

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00749 AC: 1106 AN: 147610 Hom.: 15 Cov.: 32 AF XY: 0.00726 AC XY: 522 AN XY: 71946

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00296

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000391

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000603

Gnomad4 OTH AF: 0.00438

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Mar 12, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR1: BS1, BS2 -

Apr 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30611313, 28326467, 27663056, 26972305, 23476141, 23628358, 23394784, 19807743, 19191329) -

not specified Uncertain:1 Benign:1

Nov 05, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala4290_Ala4291insThrAlaAla variant in RYR1 is classified as benign because it has been identified in 2.53% (205/8116) of African/African-American chromosomes, including 3 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA -

Jan 21, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1-related disorder Benign:2

Nov 04, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 23, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123469; hg19: chr19-39055825;