Genetic Variant NM_174934.4:c.607G>C (chr11-118137107-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_174934.4(SCN4B):c.607G>C(p.Val203Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V203M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SCN4B
NM_174934.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.28

Publications

0 publications found

Variant links:

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

SCN4B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36225504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN4B	NM_174934.4 link	c.607G>C	p.Val203Leu	missense_variant	Exon 5 of 5	ENST00000324727.9	NP_777594.1	Q8IWT1-1B0YJ93
SCN4B	NM_001142349.2 link	c.277G>C	p.Val93Leu	missense_variant	Exon 4 of 4		NP_001135821.1	Q8IWT1-2
SCN4B	NM_001142348.2 link	c.205G>C	p.Val69Leu	missense_variant	Exon 3 of 3		NP_001135820.1	Q8IWT1-3
SCN4B	NR_024527.2 link	n.596G>C		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN4B	ENST00000324727.9 link	c.607G>C	p.Val203Leu	missense_variant	Exon 5 of 5	1	NM_174934.4	ENSP00000322460.4		Q8IWT1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460812

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111056

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;.

Eigen

Benign

0.020

Eigen_PC

Benign

-0.016

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.36

T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

4.3

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.4

N;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.024

D;D

Polyphen

1.0

D;.

Vest4

0.32

MutPred

0.19

Loss of catalytic residue at V203 (P = 0.0407);.;

MVP

0.83

MPC

0.30

ClinPred

0.85

GERP RS

3.5

Varity_R

0.16

gMVP

0.36

Mutation Taster

=51/49

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over