19-35030595-C-T

Variant names:

• chr19-35030595-C-T
• rs77001837
• NM_001037.5:c.-226C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001037.5(SCN1B):​c.-226C>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 0.00723 in 152,202 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (15 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: SCN1B NM_001037.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0370
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-35030595-C-T is Benign according to our data. Variant chr19-35030595-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 675777.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00743 (1093/147180) while in subpopulation AFR AF = 0.0234 (959/41000). AF 95% confidence interval is 0.0222. There are 15 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.-226C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	ENST00000262631.11	NP_001028.1
SCN1B	NM_001037.5	c.-226C>T		5_prime_UTR_variant	Exon 1 of 6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.-226C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3		NP_950238.1
SCN1B	NM_199037.5	c.-226C>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.-226C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	1	NM_001037.5	ENSP00000262631.3
SCN1B	ENST00000262631.11	c.-226C>T		5_prime_UTR_variant	Exon 1 of 6	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1089 AN: 147074 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00486

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000228

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00933

GnomAD4 exome AF: 0.00139 AC: 7 AN: 5022 Hom.: 0 Cov.: 0 AF XY: 0.000717 AC XY: 2 AN XY: 2788

African (AFR) AF: 0.0270 AC: 2 AN: 74

American (AMR) AF: 0.0116 AC: 2 AN: 172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 96

East Asian (EAS) AF: 0.00 AC: 0 AN: 112

South Asian (SAS) AF: 0.00 AC: 0 AN: 640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 26

European-Non Finnish (NFE) AF: 0.000659 AC: 2 AN: 3034

Other (OTH) AF: 0.00340 AC: 1 AN: 294

GnomAD4 genome AF: 0.00743 AC: 1093 AN: 147180 Hom.: 15 Cov.: 31 AF XY: 0.00709 AC XY: 508 AN XY: 71694

African (AFR) AF: 0.0234 AC: 959 AN: 41000

American (AMR) AF: 0.00485 AC: 72 AN: 14844

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.000228 AC: 2 AN: 8756

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.000515 AC: 34 AN: 66054

Other (OTH) AF: 0.00923 AC: 19 AN: 2058

Alfa AF: 0.000163 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		-0.037
PromoterAI		0.045	Neutral

Splicing

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

Other links and lift over

dbSNP: rs77001837; hg19: chr19-35521499;