rs193922728

Variant names:

• chr19-35034042-G-A
• rs193922728
• ENST00000415950.5:c.751G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The ENST00000415950.5(SCN1B):​c.751G>A​(p.Val251Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000787 in 1,397,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V251V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: SCN1B ENST00000415950.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: -0.873
• Publications: 0 publications found

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]

HPN-AS1 (HGNC:47041): (HPN antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 19-35034042-G-A is Pathogenic according to our data. Variant chr19-35034042-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36757.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06659439). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.448+303G>A		intron_variant	Intron 3 of 5	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.751G>A	p.Val251Ile	missense_variant	Exon 3 of 3		NP_950238.1
SCN1B	NM_001321605.2	c.349+303G>A		intron_variant	Intron 3 of 5		NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.448+303G>A		intron_variant	Intron 3 of 5	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000646 AC: 1 AN: 154806 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000787 AC: 11 AN: 1397680 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 689494

African (AFR) AF: 0.00 AC: 0 AN: 31568

American (AMR) AF: 0.00 AC: 0 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1077370

Other (OTH) AF: 0.00 AC: 0 AN: 57934

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000484 Hom.: 0

ExAC AF: 0.0000242 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiac arrhythmia Pathogenic:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Uncertain:1

Oct 20, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: LP by LabCorp, who report the variant in 1 individual with arrhythmia. No additional reports. Only a coding change on alternative transcript - Falls within poorly conserved region of the gene -

Brugada syndrome 5 Uncertain:1

Jun 08, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SCN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 36757). This variant is present in population databases (rs193922728, ExAC 0.01%). This sequence change replaces valine with isoleucine at codon 251 of the SCN1B protein (p.Val251Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. -

not provided Uncertain:1

Nov 25, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.17
DANN	Benign	0.88
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.43	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-0.76	T
PhyloP100		-0.87
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.070	N;.
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;.
Polyphen		0.0	B;.
Vest4		0.038
MutPred		0.22		Loss of catalytic residue at V251 (P = 0.1015);.;
MVP		0.68
MPC		0.71
ClinPred		0.044	T
GERP RS		-5.6
gMVP		0.066
Mutation Taster		=98/2	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs193922728; hg19: chr19-35524946;