rs757147726

Variant names:

• chr11-118141232-T-G
• rs757147726
• NM_174934.4:c.568A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_174934.4(SCN4B):​c.568A>C​(p.Ile190Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I190I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SCN4B NM_174934.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.134
• Publications: 0 publications found

Genes affected

SCN4B (HGNC:10592): (sodium voltage-gated channel beta subunit 4) The protein encoded by this gene is one of several sodium channel beta subunits. These subunits interact with voltage-gated alpha subunits to change sodium channel kinetics. The encoded transmembrane protein forms interchain disulfide bonds with SCN2A. Defects in this gene are a cause of long QT syndrome type 10 (LQT10). Three protein-coding and one non-coding transcript variant have been found for this gene.[provided by RefSeq, Mar 2009]

SCN4B Gene-Disease associations (from GenCC):

• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• long QT syndrome 10

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1721096).
• BS2: High AC in GnomAdExome4 at 6 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4B	NM_174934.4	c.568A>C	p.Ile190Leu	missense_variant	Exon 4 of 5	ENST00000324727.9	NP_777594.1
SCN4B	NM_001142349.2	c.238A>C	p.Ile80Leu	missense_variant	Exon 3 of 4		NP_001135821.1
SCN4B	NM_001142348.2	c.166A>C	p.Ile56Leu	missense_variant	Exon 2 of 3		NP_001135820.1
SCN4B	NR_024527.2	n.557A>C		non_coding_transcript_exon_variant	Exon 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4B	ENST00000324727.9	c.568A>C	p.Ile190Leu	missense_variant	Exon 4 of 5	1	NM_174934.4	ENSP00000322460.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251474 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460808 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726734

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4870

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 10 Uncertain:1

Sep 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SCN4B-related disease. This variant is present in population databases (rs757147726, ExAC 0.009%). This sequence change replaces isoleucine with leucine at codon 190 of the SCN4B protein (p.Ile190Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.7	L;.
PhyloP100		0.13
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.27
Sift	Benign	0.096	T;D
Sift4G	Benign	0.071	T;D
Polyphen		0.0030	B;.
Vest4		0.41
MutPred		0.26		Loss of ubiquitination at K185 (P = 0.0982);.;
MVP		0.53
MPC		0.14
ClinPred		0.18	T
GERP RS		3.2
Varity_R		0.11
gMVP		0.24
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs757147726; hg19: chr11-118011947;