NM_001037.5:c.-95C>T

Variant names:

• chr19-35030726-C-T
• rs569134158
• NM_001037.5:c.-95C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001037.5(SCN1B):​c.-95C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 395,560 control chromosomes in the GnomAD database, including 7 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 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: SCN1B NM_001037.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0560
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 19-35030726-C-T is Benign according to our data. Variant chr19-35030726-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328830.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 = 0.00538 (800/148648) while in subpopulation AFR AF = 0.0186 (766/41146). AF 95% confidence interval is 0.0175. There are 7 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.-95C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	ENST00000262631.11	NP_001028.1
SCN1B	NM_001037.5	c.-95C>T		5_prime_UTR_variant	Exon 1 of 6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.-95C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3		NP_950238.1
SCN1B	NM_199037.5	c.-95C>T		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.-95C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	1	NM_001037.5	ENSP00000262631.3
SCN1B	ENST00000262631.11	c.-95C>T		5_prime_UTR_variant	Exon 1 of 6	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 800 AN: 148540 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.00147

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

GnomAD4 exome AF: 0.000316 AC: 78 AN: 246912 Hom.: 0 Cov.: 4 AF XY: 0.000230 AC XY: 33 AN XY: 143746

African (AFR) AF: 0.0127 AC: 56 AN: 4402

American (AMR) AF: 0.000413 AC: 5 AN: 12096

Ashkenazi Jewish (ASJ) AF: 0.000753 AC: 6 AN: 7964

East Asian (EAS) AF: 0.00 AC: 0 AN: 7798

South Asian (SAS) AF: 0.00 AC: 0 AN: 37736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 942

European-Non Finnish (NFE) AF: 0.0000270 AC: 4 AN: 148294

Other (OTH) AF: 0.000621 AC: 7 AN: 11272

GnomAD4 genome AF: 0.00538 AC: 800 AN: 148648 Hom.: 7 Cov.: 31 AF XY: 0.00509 AC XY: 369 AN XY: 72454

African (AFR) AF: 0.0186 AC: 766 AN: 41146

American (AMR) AF: 0.00146 AC: 22 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 5 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66508

Other (OTH) AF: 0.00338 AC: 7 AN: 2074

Alfa AF: 0.00381 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 5 Benign:1

Jan 12, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 12, 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	-0.33
CADD	Benign	20
DANN	Uncertain	0.99
PhyloP100		-0.056
PromoterAI		-0.081	Neutral
Mutation Taster		=298/2	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: rs569134158; hg19: chr19-35521630;