rs112363898

chr11-118145097-T-Achr11-118145097-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_174934.4(SCN4B):c.194A>T(p.His65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,613,998 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: SCN4B NM_174934.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0960

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026589215).
• BP6: Variant 11-118145097-T-A is Benign according to our data. Variant chr11-118145097-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190891.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN4B	NM_174934.4	c.194A>T	p.His65Leu	missense_variant	2/5	ENST00000324727.9
SCN4B	NM_001142349.2	c.-137A>T		5_prime_UTR_variant	1/4
SCN4B	NM_001142348.2	c.62-3761A>T		intron_variant
SCN4B	NR_024527.2	n.337A>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN4B	ENST00000324727.9	c.194A>T	p.His65Leu	missense_variant	2/5	1	NM_174934.4	P1
SCN4B	ENST00000415030.6	n.337A>T		non_coding_transcript_exon_variant	1/4	1
SCN4B	ENST00000529878.1	c.62-3761A>T		intron_variant		4
SCN4B	ENST00000532138.1	n.604A>T		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251480 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000194 AC: 284 AN: 1461880 Hom.: 1 Cov.: 31 AF XY: 0.000210 AC XY: 153 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74324

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000310 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2018	This variant is associated with the following publications: (PMID: 23861362, 30847666) -

Long QT syndrome 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	6.5
Dann	Benign	0.55
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.23
Sift	Benign	0.62	T
Sift4G	Benign	0.56	T
Polyphen		0.012	B
Vest4		0.23
MVP		0.030
MPC		0.18
ClinPred		0.034	T
GERP RS		-9.9
Varity_R		0.26
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs112363898; hg19: chr11-118015812;