rs72552027

chr19-35030848-G-Achr19-35030848-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001037.5(SCN1B):c.28G>A(p.Gly10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 968,158 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G10D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -0.213

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072039366).
• BP6: Variant 19-35030848-G-A is Benign according to our data. Variant chr19-35030848-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190869.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=2, Likely_benign=6}. Variant chr19-35030848-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00223 (334/149682) while in subpopulation AFR AF= 0.00771 (318/41254). AF 95% confidence interval is 0.00701. There are 6 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 332 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1B	NM_001037.5	c.28G>A	p.Gly10Ser	missense_variant	1/6	ENST00000262631.11
SCN1B	NM_199037.5	c.28G>A	p.Gly10Ser	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1B	ENST00000262631.11	c.28G>A	p.Gly10Ser	missense_variant	1/6	1	NM_001037.5	P1
SCN1B	ENST00000415950.5	c.28G>A	p.Gly10Ser	missense_variant	1/3	1
SCN1B	ENST00000638536.1	c.28G>A	p.Gly10Ser	missense_variant	1/5	1		P1
SCN1B	ENST00000595652.5	c.28G>A	p.Gly10Ser	missense_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 332 AN: 149576 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00768

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000864

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: 0.00145

GnomAD3 exomes AF: 0.00169 AC: 1 AN: 592 Hom.: 0 AF XY: 0.00267 AC XY: 1 AN XY: 374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00962

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000184 AC: 151 AN: 818476 Hom.: 0 Cov.: 11 AF XY: 0.000138 AC XY: 54 AN XY: 392200

Gnomad4 AFR exome AF: 0.00876

Gnomad4 AMR exome AF: 0.000689

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: 0.00000282

Gnomad4 OTH exome AF: 0.000302

GnomAD4 genome AF: 0.00223 AC: 334 AN: 149682 Hom.: 6 Cov.: 31 AF XY: 0.00220 AC XY: 161 AN XY: 73042

Gnomad4 AFR AF: 0.00771

Gnomad4 AMR AF: 0.000862

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: 0.00144

Alfa AF: 0.000143 Hom.: 0

ExAC AF: 0.0000556 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2019	Reported in one African American infant with sudden infant death sydnrome (SIDS) and in one healthy, ethnically-matched control individual (Tan et al., 2010); Reported in one patient with LQTS (Rurio et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24662403, 20226894) -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 17, 2016	Variant summary: The SCN1B c.28G>A (p.Gly10Ser) variant involves the alteration of a non-conserved nucleotide, is not located in a known functional domain, and 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 16/5008 control chromosomes, predominantly observed in the African subpopulation (16/1322 African alleles from 1000G; 0.01210). This frequency is significantly greater than the estimated maximal expected allele frequency of a pathogenic SCN1B variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. However, the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site. The variant was identified in one SIDS case (also found in healthy African American adult control) and one LQTS patient without evidence of causality (i.e. co-segregation). In addition, one clinical diagnostic laboratory classified this variant as a VUS. Taken together and based on the allele frequency in the African subpopulation, this variant is classified as Likely Benign until additional information is available. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -

Brugada syndrome 5 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

SCN1B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Generalized epilepsy with febrile seizures plus, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2018

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	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.068	T;T;.;.
Eigen	Benign	0.017
Eigen_PC	Benign	-0.050
FATHMM_MKL	Benign	0.26	N
MetaRNN	Benign	0.0072	T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	0.0	N;N;N;.
MutationTaster	Benign	0.95	N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.65	N;.;N;.
REVEL	Benign	0.25
Sift	Benign	0.36	T;.;D;.
Sift4G	Benign	0.40	T;.;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.094
MutPred		0.36		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.97
MPC		0.67
ClinPred		0.11	T
GERP RS		2.0
Varity_R		0.067
gMVP		0.52

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: rs72552027; hg19: chr19-35521752;