rs1060501126

chr3-38579357-G-Achr3-38579357-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_001099404.2(SCN5A):c.3367C>T(p.Pro1123Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1123L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.526

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCN5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.08385798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3367C>T	p.Pro1123Ser	missense_variant	18/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3364C>T	p.Pro1122Ser	missense_variant	18/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3367C>T	p.Pro1123Ser	missense_variant	18/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3364C>T	p.Pro1122Ser	missense_variant	18/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1442844 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715298

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	0.078
CardioboostArm	Benign	0.000055
CardioboostCm	Benign	0.0014
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	14
Dann	Benign	0.79
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.50	N
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.084	T;T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PROVEAN	Benign	-0.62	N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.72	T;T;T;T;T;T
Sift4G	Benign	0.83	T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;B
Vest4		0.080
MutPred		0.36		Loss of catalytic residue at P1123 (P = 0.0256);.;Loss of catalytic residue at P1123 (P = 0.0256);Loss of catalytic residue at P1123 (P = 0.0256);Loss of catalytic residue at P1123 (P = 0.0256);.;
MVP		0.72
MPC		0.030
ClinPred		0.034	T
GERP RS		1.5
Varity_R		0.044
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060501126; hg19: chr3-38620848;