rs398123469

chr19-38565185-GCACGGCGGC-Gchr19-38565185-GCACGGCGGC-GCACGGCGGCCACGGCGGCchr19-38565185-GCACGGCGGC-GCACGGCGGCCACGGCGGCCACGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BP6 BS1

The NM_000540.3(RYR1):c.12861_12869del(p.Thr4288_Ala4290del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 1,117,954 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: RYR1 NM_000540.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.70

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 Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000540.3
• BP6: Variant 19-38565185-GCACGGCGGC-G is Benign according to our data. Variant chr19-38565185-GCACGGCGGC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285661.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00271 (400/147618) while in subpopulation AFR AF= 0.00909 (373/41046). AF 95% confidence interval is 0.00833. There are 1 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.12861_12869del	p.Thr4288_Ala4290del	inframe_deletion	91/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.12861_12869del	p.Thr4288_Ala4290del	inframe_deletion	91/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 398 AN: 147512 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00906

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000809

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000106

Gnomad OTH AF: 0.00197

GnomAD3 exomes AF: 0.000391 AC: 1 AN: 2558 Hom.: 0 AF XY: 0.000567 AC XY: 1 AN XY: 1764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad SAS exome AF: 0.00305

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000302 AC: 293 AN: 970336 Hom.: 1 AF XY: 0.000302 AC XY: 138 AN XY: 456652

Gnomad4 AFR exome AF: 0.00929

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000902

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000718

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.00271 AC: 400 AN: 147618 Hom.: 1 Cov.: 32 AF XY: 0.00278 AC XY: 200 AN XY: 71954

Gnomad4 AFR AF: 0.00909

Gnomad4 AMR AF: 0.000808

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000106

Gnomad4 OTH AF: 0.00195

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2016	- -

RYR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2023

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). -

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;