rs794728934

Positions:

• chr3-38557225-A-G
• chr3-38557225-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001099404.2(SCN5A):​c.4299+6T>C variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00000342 in 1,461,380 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN5A NM_001099404.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.7858
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.10

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-38557225-A-G is Pathogenic according to our data. Variant chr3-38557225-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201588.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.4296+6T>C		splice_donor_region_variant, intron_variant		ENST00000423572.7
SCN5A	NM_001099404.2	c.4299+6T>C		splice_donor_region_variant, intron_variant		ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4299+6T>C		splice_donor_region_variant, intron_variant		5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4296+6T>C		splice_donor_region_variant, intron_variant		1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461380 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726992

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 20, 2021	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 201588). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 24 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein, but it affects a nucleotide within the consensus splice site of the intron. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2012	c.4299+6 T>C: c.4299+6 T>C:IVS24+6 T>C in intron 24 of the SCN5A gene (NM_198056.2) Although the IVS24+6 T>C mutation in the SCN5A gene has not been reported previously to our knowledge, the mutation destroys the splice donor site of intron 24 and is expected to cause abnormal gene splicing. IVS24+6 T>C is predicted by several splice site prediction algorithms to destroy the splice-donor site of intron 24 leading to abnormal gene splicing. The mutation is predicted to lead to either an abnormal message, which is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Therefore, IVS24+6 T>C in the SCN5A gene is interpreted as a disease-causing mutation. The variant is found in BRUGADA,LQT panel(s). -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 06, 2022

This variant causes a T to C nucleotide substitution at the +6 position of intron 24 of the SCN5A gene. Splice prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	13
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.79
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.72		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794728934; hg19: chr3-38598716;