NM_001037.5:c.-9C>A

Variant names:

• chr19-35030812-C-A
• rs66671189
• NM_001037.5:c.-9C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001037.5(SCN1B):​c.-9C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,079,936 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: SCN1B NM_001037.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.52
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-35030812-C-A is Benign according to our data. Variant chr19-35030812-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 139002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00542 (809/149144) while in subpopulation AFR AF = 0.0188 (775/41126). AF 95% confidence interval is 0.0177. There are 6 homozygotes in GnomAd4. There are 374 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.-9C>A		5_prime_UTR_variant	Exon 1 of 6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.-9C>A		5_prime_UTR_variant	Exon 1 of 3		NP_950238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.-9C>A		5_prime_UTR_variant	Exon 1 of 6	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 809 AN: 149042 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.00146

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: 0.00341

GnomAD2 exomes AF: 0.000502 AC: 7 AN: 13934 AF XY: 0.000476

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.000363

Gnomad ASJ exome AF: 0.000772

Gnomad EAS 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: 0.000392 AC: 365 AN: 930792 Hom.: 5 Cov.: 13 AF XY: 0.000334 AC XY: 153 AN XY: 458422

African (AFR) AF: 0.0172 AC: 298 AN: 17278

American (AMR) AF: 0.000488 AC: 4 AN: 8198

Ashkenazi Jewish (ASJ) AF: 0.000843 AC: 9 AN: 10680

East Asian (EAS) AF: 0.00 AC: 0 AN: 13382

South Asian (SAS) AF: 0.0000468 AC: 2 AN: 42708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2312

European-Non Finnish (NFE) AF: 0.0000115 AC: 9 AN: 783464

Other (OTH) AF: 0.00126 AC: 43 AN: 34138

GnomAD4 genome AF: 0.00542 AC: 809 AN: 149144 Hom.: 6 Cov.: 31 AF XY: 0.00514 AC XY: 374 AN XY: 72734

African (AFR) AF: 0.0188 AC: 775 AN: 41126

American (AMR) AF: 0.00146 AC: 22 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 5 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5052

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66810

Other (OTH) AF: 0.00337 AC: 7 AN: 2076

Alfa AF: 0.0000699 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 08, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 06, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Apr 06, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: This c.-9C>A variant affects a non-conserved nucleotide, located in the 5' UTR, a location that could affect transcription, however, no functional studies have been performed to assess this. The variant of interest was observed in a control population (1000 Gs) with an allele frequency of 38/5008, predominantly in African cohort with an allele frequency of 0.026 (34/1322 chromosomes). This frequency exceeds the predicted maximum expected allele frequency for a pathogenic SCN1B allele (0.00001), suggesting this variant is benign. In addition, Multiple clinical laboratories have classified this variant as benign. Taken together, this variant has been classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Brugada syndrome 5 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.1
DANN	Benign	0.93
PhyloP100		-1.5
PromoterAI		0.078	Neutral
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs66671189; hg19: chr19-35521716;