1-237610757-G-C

Position:

chr1-237610757-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001035.3(RYR2):c.4684-5G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,593,286 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 42 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 40 hom. )

Consequence

RYR2
NM_001035.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0005525

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.0310

Variant links:

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

RYR2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 1-237610757-G-C is Benign according to our data. Variant chr1-237610757-G-C is described in ClinVar as [Benign]. Clinvar id is 43792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-237610757-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0124 (1881/152066) while in subpopulation AFR AF= 0.0412 (1708/41466). AF 95% confidence interval is 0.0396. There are 42 homozygotes in gnomad4. There are 903 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1881 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.4684-5G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.4684-5G>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_001035.3	ENSP00000355533	P1	Q92736-1
RYR2	ENST00000659194.3 linkuse as main transcript	c.4684-5G>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			ENSP00000499653
RYR2	ENST00000660292.2 linkuse as main transcript	c.4684-5G>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			ENSP00000499787
RYR2	ENST00000609119.2 linkuse as main transcript	c.4684-5G>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	5		ENSP00000499659

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1876

AN:

151948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00485

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00618

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00910

GnomAD3 exomes

AF:

0.00371

AC:

835

AN:

224958

Hom.:

AF XY:

0.00294

AC XY:

356

AN XY:

121258

show subpopulations

Gnomad AFR exome

AF:

0.0424

Gnomad AMR exome

AF:

0.00273

Gnomad ASJ exome

AF:

0.00263

Gnomad EAS exome

AF:

0.00561

Gnomad SAS exome

AF:

0.0000725

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000496

Gnomad OTH exome

AF:

0.00160

GnomAD4 exome

AF:

0.00160

AC:

2309

AN:

1441220

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1027

AN XY:

714658

show subpopulations

Gnomad4 AFR exome

AF:

0.0435

Gnomad4 AMR exome

AF:

0.00284

Gnomad4 ASJ exome

AF:

0.00253

Gnomad4 EAS exome

AF:

0.00282

Gnomad4 SAS exome

AF:

0.0000959

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.000300

Gnomad4 OTH exome

AF:

0.00352

GnomAD4 genome

AF:

0.0124

AC:

1881

AN:

152066

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

903

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0412

Gnomad4 AMR

AF:

0.00484

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00601

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00391

Hom.:

Bravo

AF:

0.0139

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 14, 2012	4684-5G>C in intron 35 of RYR2: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence and ha s been identified in 3.2% (98/3078) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS; dbSNP rs7522981). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 20, 2018

- -

Arrhythmogenic right ventricular dysplasia 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.5

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00055

dbscSNV1_RF

Benign

0.024

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over