rs28365109

Variant names:

• chr19-35039621-C-A
• rs28365109
• NM_001037.5:c.591-14C>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.591-14C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,614,010 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (15 hom., cov: 32)
  • Exomes 𝑓: 0.014 (182 hom.)
• Consequence: SCN1B NM_001037.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.00600
• Publications: 7 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 19-35039621-C-A is Benign according to our data. Variant chr19-35039621-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00951 (1448/152300) while in subpopulation SAS AF = 0.0191 (92/4824). AF 95% confidence interval is 0.0159. There are 15 homozygotes in GnomAd4. There are 658 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	NM_001037.5	MANE Select	c.591-14C>A		intron	N/A	NP_001028.1
	SCN1B	NM_001321605.2		c.492-14C>A		intron	N/A	NP_001308534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.591-14C>A		intron	N/A	ENSP00000262631.3
	SCN1B	ENST00000638536.1	TSL:1	c.591-14C>A		intron	N/A	ENSP00000492022.1
	SCN1B	ENST00000602150.2	TSL:2	n.2723C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00950 AC: 1445 AN: 152182 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0112 AC: 2822 AN: 251362 AF XY: 0.0123

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0144 AC: 21009 AN: 1461710 Hom.: 182 Cov.: 31 AF XY: 0.0147 AC XY: 10662 AN XY: 727168

African (AFR) AF: 0.00278 AC: 93 AN: 33480

American (AMR) AF: 0.00566 AC: 253 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 428 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0190 AC: 1640 AN: 86258

European-Finnish (FIN) AF: 0.00279 AC: 149 AN: 53416

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5768

European-Non Finnish (NFE) AF: 0.0159 AC: 17625 AN: 1111842

Other (OTH) AF: 0.0122 AC: 737 AN: 60392

GnomAD4 genome AF: 0.00951 AC: 1448 AN: 152300 Hom.: 15 Cov.: 32 AF XY: 0.00884 AC XY: 658 AN XY: 74468

African (AFR) AF: 0.00318 AC: 132 AN: 41560

American (AMR) AF: 0.00582 AC: 89 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4824

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0149 AC: 1014 AN: 68016

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0126 Hom.: 2

Bravo AF: 0.00884

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Brugada syndrome 5 (2)
-	-	1	Generalized epilepsy with febrile seizures plus, type 1 (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 1;C2748541:Brugada syndrome 5;C3809311:Atrial fibrillation, familial, 13;C4479236:Developmental and epileptic encephalopathy, 52 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		-0.0060
Mutation Taster		=100/0	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: rs28365109; hg19: chr19-35530525;