19-38496278-C-T

Position:

• chr19-38496278-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_000540.3(RYR1):​c.6612C>T​(p.His2204His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,982 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: RYR1 NM_000540.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.45

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 19-38496278-C-T is Benign according to our data. Variant chr19-38496278-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00162 (246/152268) while in subpopulation AFR AF= 0.00546 (227/41560). AF 95% confidence interval is 0.00488. There are 1 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.6612C>T	p.His2204His	synonymous_variant	40/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.6612C>T	p.His2204His	synonymous_variant	40/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.6612C>T	p.His2204His	synonymous_variant	40/105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.63C>T		non_coding_transcript_exon_variant	1/49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.6612C>T		non_coding_transcript_exon_variant	40/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000414 AC: 104 AN: 251240 Hom.: 0 AF XY: 0.000331 AC XY: 45 AN XY: 135814

Gnomad AFR exome AF: 0.00536

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000187 AC: 274 AN: 1461714 Hom.: 1 Cov.: 32 AF XY: 0.000182 AC XY: 132 AN XY: 727152

Gnomad4 AFR exome AF: 0.00538

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74450

Gnomad4 AFR AF: 0.00546

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000836 Hom.: 1

Bravo AF: 0.00178

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2017

- -

RYR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Malignant hyperthermia, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2021

This variant is associated with the following publications: (PMID: 28952030) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.22
DANN	Benign	0.58

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: rs141646642; hg19: chr19-38986918;