rs752177520

chr19-38473739-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_000540.3(RYR1):c.4128G>A(p.Lys1376=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 1,525,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-38473739-G-A is Benign according to our data. Variant chr19-38473739-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 544521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.14 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.4128G>A	p.Lys1376=	synonymous_variant	28/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.4128G>A	p.Lys1376=	synonymous_variant	28/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.4128G>A	p.Lys1376=	synonymous_variant	28/105	1		P4
RYR1	ENST00000599547.6	c.4128G>A	p.Lys1376=	synonymous_variant, NMD_transcript_variant	28/80	2

Frequencies

GnomAD3 genomes AF: 0.0000139 AC: 2 AN: 144354 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000308

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000147 AC: 2 AN: 136336 Hom.: 0 AF XY: 0.0000269 AC XY: 2 AN XY: 74278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000453

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000204

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000579 AC: 8 AN: 1380776 Hom.: 0 Cov.: 33 AF XY: 0.00000882 AC XY: 6 AN XY: 680394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000561

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000139 AC: 2 AN: 144354 Hom.: 0 Cov.: 31 AF XY: 0.0000284 AC XY: 2 AN XY: 70504

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000308

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RYR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 22, 2021

- -

Malignant hyperthermia, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	5.5
Dann	Benign	0.51

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: rs752177520; hg19: chr19-38964379; COSMIC: COSV62109951;