19-38565185-GCACGGCGGC-GCACGGCGGCCACGGCGGC

Position:

• chr19-38565185-GCACGGCGGC-GCACGGCGGCCACGGCGGC

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_12869dup​(p.Thr4288_Ala4290dup) variant causes a 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 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/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12861_12869dup	p.Thr4288_Ala4290dup	inframe_insertion	91/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12861_12869dup	p.Thr4288_Ala4290dup	inframe_insertion	91/106	5	NM_000540.3	ENSP00000352608	A2

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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RYR1: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2018	This variant is associated with the following publications: (PMID: 30611313, 28326467, 27663056, 26972305, 23476141, 23628358, 23394784, 19807743, 19191329) -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 05, 2021	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 -

RYR1-related disorder Benign:2

Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 04, 2021	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). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2019

- -

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;