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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174934.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4B	NM_174934.4	MANE Select	c.568A>C	p.Ile190Leu	missense	Exon 4 of 5	NP_777594.1
	SCN4B	NM_001142349.2		c.238A>C	p.Ile80Leu	missense	Exon 3 of 4	NP_001135821.1
	SCN4B	NM_001142348.2		c.166A>C	p.Ile56Leu	missense	Exon 2 of 3	NP_001135820.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN4B	ENST00000324727.9	TSL:1 MANE Select	c.568A>C	p.Ile190Leu	missense	Exon 4 of 5	ENSP00000322460.4
	SCN4B	ENST00000415030.6	TSL:1	n.711A>C		non_coding_transcript_exon	Exon 3 of 4
	SCN4B	ENST00000531550.1	TSL:1	n.633A>C		non_coding_transcript_exon	Exon 1 of 2

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Long QT syndrome 10 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.7	L
PhyloP100		0.13
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.27
Sift	Benign	0.096	T
Sift4G	Benign	0.071	T
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;