chr19-38440938-G-C

Position:

• chr19-38440938-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000540.3(RYR1):​c.165+74G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,526,286 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0065 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (156 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.717

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.165+74G>C		intron_variant		ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.165+74G>C		intron_variant		5	NM_000540.3	ENSP00000352608	A2
RYR1	ENST00000355481.8	c.165+74G>C		intron_variant		1		ENSP00000347667	P4
RYR1	ENST00000599547.6	c.165+74G>C		intron_variant, NMD_transcript_variant		2		ENSP00000471601

Frequencies

GnomAD3 genomes AF: 0.00647 AC: 982 AN: 151884 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00381

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0939

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00471

Gnomad OTH AF: 0.00481

GnomAD4 exome AF: 0.00685 AC: 9410 AN: 1374284 Hom.: 156 AF XY: 0.00673 AC XY: 4574 AN XY: 679944

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.000447

Gnomad4 EAS exome AF: 0.0780

Gnomad4 SAS exome AF: 0.00401

Gnomad4 FIN exome AF: 0.00198

Gnomad4 NFE exome AF: 0.00499

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.00646 AC: 982 AN: 152002 Hom.: 27 Cov.: 32 AF XY: 0.00683 AC XY: 507 AN XY: 74282

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00380

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0941

Gnomad4 SAS AF: 0.00561

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00471

Gnomad4 OTH AF: 0.00476

Alfa AF: 0.00434 Hom.: 1

Bravo AF: 0.00652

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs2304145; hg19: chr19-38931578; COSMIC: COSV62107593;