19-35030820-C-T

Position:

• chr19-35030820-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001037.5(SCN1B):​c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000185 in 1,082,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: SCN1B NM_001037.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.175

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.-1C>T		5_prime_UTR_variant	1/6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.-1C>T		5_prime_UTR_variant	1/3		NP_950238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.-1C>T		5_prime_UTR_variant	1/6	1	NM_001037.5	ENSP00000262631	P1
SCN1B	ENST00000415950.5	c.-1C>T		5_prime_UTR_variant	1/3	1		ENSP00000396915
SCN1B	ENST00000638536.1	c.-1C>T		5_prime_UTR_variant	1/5	1		ENSP00000492022	P1
SCN1B	ENST00000595652.5	c.-1C>T		5_prime_UTR_variant	1/6	2		ENSP00000468848

Frequencies

GnomAD3 genomes AF: 0.00000670 AC: 1 AN: 149184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000107 AC: 1 AN: 933330 Hom.: 0 Cov.: 13 AF XY: 0.00000219 AC XY: 1 AN XY: 456526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000141

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 AF: 0.00000670 AC: 1 AN: 149184 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72742

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2016

A variant of uncertain significance has been identified in the SCN1B gene. The c.-1 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although the c.-1 C>T variant was not observed in approximately 1,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, the data was noted to have reduced depth of sequencing reads and therefore may be unreliable. It occurs at a position that is conserved in mammals. This substitution alters a position in the Kozak sequence, which is located in the 5' untranslated region (UTR) of the gene and plays a role in the initiation of protein translation. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Additionally, variants in the 5' UTR of the SCN1B gene have not been reported in the Human Gene Mutation Database (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.-1C>T variant is located in the 5' untranslated region (5’ UTR) of the SCN1B gene. This variant results from a C to T substitution 1 nucleotide upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.95

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: rs1057518527; hg19: chr19-35521724;