rs187531872

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The ENST00000423572.7(SCN5A):​c.998+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000103 in 1,595,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

SCN5A
ENST00000423572.7 splice_donor_5th_base, intron

Scores

2
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 6.80
Variant links:
Genes affected
SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 3-38608146-C-T is Benign according to our data. Variant chr3-38608146-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165158.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}. Variant chr3-38608146-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN5ANM_000335.5 linkuse as main transcriptc.998+5G>A splice_donor_5th_base_variant, intron_variant ENST00000423572.7 NP_000326.2
SCN5ANM_001099404.2 linkuse as main transcriptc.998+5G>A splice_donor_5th_base_variant, intron_variant ENST00000413689.6 NP_001092874.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN5AENST00000413689.6 linkuse as main transcriptc.998+5G>A splice_donor_5th_base_variant, intron_variant 5 NM_001099404.2 ENSP00000410257 P4
SCN5AENST00000423572.7 linkuse as main transcriptc.998+5G>A splice_donor_5th_base_variant, intron_variant 1 NM_000335.5 ENSP00000398266 A1Q14524-2

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
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:
0.00113
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000189
AC:
47
AN:
249120
Hom.:
0
AF XY:
0.000170
AC XY:
23
AN XY:
135142
show subpopulations
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:
0.00
Gnomad FIN exome
AF:
0.00149
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.000331
GnomAD4 exome
AF:
0.0000963
AC:
139
AN:
1443472
Hom.:
0
Cov.:
27
AF XY:
0.000110
AC XY:
79
AN XY:
719484
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00133
Gnomad4 NFE exome
AF:
0.0000539
Gnomad4 OTH exome
AF:
0.000134
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.000256
AC XY:
19
AN XY:
74354
show subpopulations
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:
0.00113
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000252
Hom.:
0
Bravo
AF:
0.0000529

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 07, 2019The 998+5G>A variant in SCN5A has not been reported in individuals with cardiomyopathy, but it has been identified in 1/8366 of European American chromosomes by the NHLBI Exome Sequencing Project and in 0.5% (1/186) of Finnish chromosomes by the 1000 Genomes Project (http://evs.gs.washington.edu/EVS/;dbSNP rs187531872). This variant is located in the 5' splice region. Computational tools suggest a possible impact to splicing. However, this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of the 998+5G>A variant. 998+5G>A intron 8 of SCN5A (rs187531872; allele frequency = 1/8366). This variant has been seen by several clinical labs in ClinVar (uncertain significance), and affects splice in silico. This variant has been reported in an individual affected with long QT syndrome (PMID: 23631430). -
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsJan 29, 2015- -
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterresearchKlaassen Lab, Charite University Medicine BerlinJul 03, 2019- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 14, 2021This alteration is classified as likely 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. -
Cardiac arrhythmia Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 15, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.18
CADD
Benign
21
DANN
Benign
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.34
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.34
Position offset: 5

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.

Other links and lift over

dbSNP: rs187531872; hg19: chr3-38649637; API