19-38453088-G-C

Variant names:

• chr19-38453088-G-C
• rs12460768
• NM_000540.3:c.1440+74G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000540.3(RYR1):​c.1440+74G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,493,130 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 28)
  • Exomes 𝑓: 0.0027 (29 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.86

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=-0.83).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00224 (338/151198) while in subpopulation SAS AF= 0.00775 (37/4772). AF 95% confidence interval is 0.00578. There are 2 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.1440+74G>C		intron_variant	Intron 13 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.1440+74G>C		intron_variant	Intron 13 of 105	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.1440+74G>C		intron_variant	Intron 13 of 104	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.1440+74G>C		intron_variant	Intron 13 of 79	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 339 AN: 151082 Hom.: 2 Cov.: 28

Gnomad AFR AF: 0.000439

Gnomad AMI AF: 0.00222

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00775

Gnomad FIN AF: 0.00248

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00337

GnomAD4 exome AF: 0.00266 AC: 3568 AN: 1341932 Hom.: 29 AF XY: 0.00291 AC XY: 1945 AN XY: 668050

Gnomad4 AFR exome AF: 0.000514

Gnomad4 AMR exome AF: 0.000510

Gnomad4 ASJ exome AF: 0.000202

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.00913

Gnomad4 FIN exome AF: 0.00172

Gnomad4 NFE exome AF: 0.00252

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00224 AC: 338 AN: 151198 Hom.: 2 Cov.: 28 AF XY: 0.00226 AC XY: 167 AN XY: 73804

Gnomad4 AFR AF: 0.000438

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00775

Gnomad4 FIN AF: 0.00248

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.00257 Hom.: 1495

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.36
DANN	Benign	0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs12460768; hg19: chr19-38943728;