19-35032621-G-T

Variant names:

• chr19-35032621-G-T
• NM_001037.5:c.134G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001037.5(SCN1B):​c.134G>T​(p.Arg45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,796 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59

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 3 ACMG points.

• PM1: In a disulfide_bond (size 81) in uniprot entity SCN1B_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001037.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31342918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.134G>T	p.Arg45Leu	missense_variant	Exon 2 of 6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.134G>T	p.Arg45Leu	missense_variant	Exon 2 of 3		NP_950238.1
SCN1B	NM_001321605.2	c.35G>T	p.Arg12Leu	missense_variant	Exon 2 of 6		NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.134G>T	p.Arg45Leu	missense_variant	Exon 2 of 6	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;.;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.6	L;L;L;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;.;D;.;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.018	D;.;D;.;.;.
Sift4G	Uncertain	0.045	D;.;D;T;.;.
Polyphen		0.83	P;P;P;D;.;.
Vest4		0.41
MutPred		0.50		Loss of phosphorylation at S47 (P = 0.0516);Loss of phosphorylation at S47 (P = 0.0516);Loss of phosphorylation at S47 (P = 0.0516);Loss of phosphorylation at S47 (P = 0.0516);.;.;
MVP		0.94
MPC		1.3
ClinPred		0.89	D
GERP RS		2.8
Varity_R		0.59
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-35523525;