rs16969930

Positions:

chr19-35039169-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001037.5(SCN1B):c.501T>C(p.Ile167Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,614,122 control chromosomes in the GnomAD database, including 756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 49 hom., cov: 32)

Exomes 𝑓: 0.029 ( 707 hom. )

Consequence

SCN1B
NM_001037.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.00200

Variant links:

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]

SCN1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 19-35039169-T-C is Benign according to our data. Variant chr19-35039169-T-C is described in ClinVar as [Benign]. Clinvar id is 130210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35039169-T-C is described in Lovd as [Benign]. Variant chr19-35039169-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.002 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0198 (3014/152282) while in subpopulation SAS AF= 0.0338 (163/4824). AF 95% confidence interval is 0.0297. There are 49 homozygotes in gnomad4. There are 1370 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3014 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5 link	c.501T>C	p.Ile167Ile	synonymous_variant	4/6	ENST00000262631.11	NP_001028.1	Q07699-1
SCN1B	NM_001321605.2 link	c.402T>C	p.Ile134Ile	synonymous_variant	4/6		NP_001308534.1	Q07699A0A1W2PR05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11 link	c.501T>C	p.Ile167Ile	synonymous_variant	4/6	1	NM_001037.5	ENSP00000262631.3		Q07699-1

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3013

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00594

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0340

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0308

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0231

AC:

5811

AN:

251484

Hom.:

AF XY:

0.0248

AC XY:

3370

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.00919

Gnomad ASJ exome

AF:

0.0319

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0343

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.0316

Gnomad OTH exome

AF:

0.0238

GnomAD4 exome

AF:

0.0292

AC:

42669

AN:

1461840

Hom.:

707

Cov.:

AF XY:

0.0294

AC XY:

21368

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00517

Gnomad4 AMR exome

AF:

0.0100

Gnomad4 ASJ exome

AF:

0.0307

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0337

Gnomad4 FIN exome

AF:

0.0130

Gnomad4 NFE exome

AF:

0.0324

Gnomad4 OTH exome

AF:

0.0248

GnomAD4 genome

AF:

0.0198

AC:

3014

AN:

152282

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1370

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00592

Gnomad4 AMR

AF:

0.0120

Gnomad4 ASJ

AF:

0.0349

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0338

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.0308

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0262

Hom.:

Bravo

AF:

0.0183

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0322

EpiControl

AF:

0.0321

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Brugada syndrome 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Generalized epilepsy with febrile seizures plus, type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2015

This alteration is classified as 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

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.0

DANN

Benign

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over