19-35039191-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001037.5(SCN1B):c.523G>C(p.Val175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V175M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02

Genes affected

SCN1B (HGNC:10586): (sodium voltage-gated channel beta subunit 1) Voltage-gated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells. They are composed of one alpha and two beta subunits, where the alpha subunit provides channel activity and the beta-1 subunit modulates the kinetics of channel inactivation. This gene encodes a sodium channel beta-1 subunit. Mutations in this gene result in generalized epilepsy with febrile seizures plus, Brugada syndrome 5, and defects in cardiac conduction. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.100210816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.523G>C	p.Val175Leu	missense_variant	4/6	ENST00000262631.11
SCN1B	NM_001321605.2	c.424G>C	p.Val142Leu	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.523G>C	p.Val175Leu	missense_variant	4/6	1	NM_001037.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727218

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.: 32

ExAC AF: 0.0000741 AC: 9

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	23
Dann	Benign	0.91
DEOGEN2	Benign	0.070	T;T;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.66	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.060	N;N;.;.
MutationTaster	Benign	0.64	D
PROVEAN	Benign	0.43	N;.;.;.
REVEL	Uncertain	0.36
Sift	Benign	1.0	T;.;.;.
Sift4G	Benign	1.0	T;.;T;.
Polyphen		0.0	B;B;B;.
Vest4		0.17
MutPred		0.39		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;
MVP		0.84
ClinPred		0.12	T
GERP RS		4.1
Varity_R		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs776213428; hg19: chr19-35530095;