chr19-38502855-C-T

Variant names:

• chr19-38502855-C-T
• rs201945985
• NM_000540.3:c.7836-25C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000540.3(RYR1):​c.7836-25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,605,252 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00059 (5 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.896

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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-38502855-C-T is Benign according to our data. Variant chr19-38502855-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000438 (66/150736) while in subpopulation SAS AF= 0.00409 (19/4650). AF 95% confidence interval is 0.00267. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7836-25C>T		intron_variant	Intron 48 of 105	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7836-25C>T		intron_variant	Intron 48 of 105	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7836-25C>T		intron_variant	Intron 48 of 104	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.1287-25C>T		intron_variant	Intron 9 of 48	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7836-25C>T		intron_variant	Intron 48 of 79	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes AF: 0.000438 AC: 66 AN: 150620 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000789

Gnomad SAS AF: 0.00408

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000326

Gnomad OTH AF: 0.000486

GnomAD3 exomes AF: 0.00117 AC: 287 AN: 245408 Hom.: 1 AF XY: 0.00142 AC XY: 189 AN XY: 133164

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000382

Gnomad SAS exome AF: 0.00749

Gnomad FIN exome AF: 0.0000560

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000593 AC: 862 AN: 1454516 Hom.: 5 Cov.: 33 AF XY: 0.000786 AC XY: 569 AN XY: 723800

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00665

Gnomad4 FIN exome AF: 0.0000211

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.000697

GnomAD4 genome AF: 0.000438 AC: 66 AN: 150736 Hom.: 0 Cov.: 29 AF XY: 0.000421 AC XY: 31 AN XY: 73654

Gnomad4 AFR AF: 0.000219

Gnomad4 AMR AF: 0.000661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000791

Gnomad4 SAS AF: 0.00409

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000326

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000598 Hom.: 0

Bravo AF: 0.000521

Asia WGS AF: 0.00231 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.5
DANN	Benign	0.44
BranchPoint Hunter		2.0

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: rs201945985; hg19: chr19-38993495;