3-38576780-G-T

Position:

• chr3-38576780-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PP2 PP5 BP4

The NM_000335.5(SCN5A):​c.3389C>A​(p.Thr1130Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in Lovd as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN5A NM_000335.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001208
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191

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]

SCN5A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 267) in uniprot entity SCN5A_HUMAN there are 26 pathogenic changes around while only 11 benign (70%) in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
• PP5: Variant 3-38576780-G-T is Pathogenic according to our data. Variant chr3-38576780-G-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.109472334). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3392C>A	p.Thr1131Asn	missense_variant, splice_region_variant	19/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3389C>A	p.Thr1130Asn	missense_variant, splice_region_variant	19/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3392C>A	p.Thr1131Asn	missense_variant, splice_region_variant	19/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3389C>A	p.Thr1130Asn	missense_variant, splice_region_variant	19/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455942 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723518

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
CardioboostCm	Benign	0.0022
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	7.2
DANN	Benign	0.70
DEOGEN2	Benign	0.35	.;.;.;.;.;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.58	.;T;T;T;T;T;T;.;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.34	.;.;.;.;.;N;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.030	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.53	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T;T;T;T;T
Polyphen		0.056	B;B;.;B;.;B;B;.;.
Vest4		0.13
MutPred		0.47		Loss of phosphorylation at T1131 (P = 0.0058);.;Loss of phosphorylation at T1131 (P = 0.0058);Loss of phosphorylation at T1131 (P = 0.0058);.;Loss of phosphorylation at T1131 (P = 0.0058);.;.;.;
MVP		0.72
MPC		0.032
ClinPred		0.093	T
GERP RS		0.16
Varity_R		0.040
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0020
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: rs199473197; hg19: chr3-38618271;