rs3746255

Variant names:

• chr19-35033642-C-T
• rs3746255
• NM_001037.5:c.351C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001037.5(SCN1B):​c.351C>T​(p.Gly117Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,200 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene SCN1B is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (24 hom.)
• Consequence: SCN1B NM_001037.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.25
• Publications: 10 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

Specifications for SCN1B are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 19-35033642-C-T is Benign according to our data. Variant chr19-35033642-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00115 (175/152316) while in subpopulation EAS AF = 0.0266 (138/5186). AF 95% confidence interval is 0.023. There are 1 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AD,AR,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	NM_001037.5	MANE Select	c.351C>T	p.Gly117Gly	synonymous	Exon 3 of 6	NP_001028.1	Q07699-1
	SCN1B	NM_199037.5		c.351C>T	p.Gly117Gly	synonymous	Exon 3 of 3	NP_950238.1	Q07699-2
	SCN1B	NM_001321605.2		c.252C>T	p.Gly84Gly	synonymous	Exon 3 of 6	NP_001308534.1	A0A1W2PR05

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.351C>T	p.Gly117Gly	synonymous	Exon 3 of 6	ENSP00000262631.3	Q07699-1
	SCN1B	ENST00000415950.5	TSL:1	c.351C>T	p.Gly117Gly	synonymous	Exon 3 of 3	ENSP00000396915.2	Q07699-2
	SCN1B	ENST00000638536.1	TSL:1	c.351C>T	p.Gly117Gly	synonymous	Exon 3 of 5	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0267

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00247 AC: 620 AN: 251492 AF XY: 0.00247

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0285

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00118 AC: 1727 AN: 1461884 Hom.: 24 Cov.: 33 AF XY: 0.00125 AC XY: 908 AN XY: 727246

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0330 AC: 1309 AN: 39700

South Asian (SAS) AF: 0.00284 AC: 245 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1112004

Other (OTH) AF: 0.00190 AC: 115 AN: 60396

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74466

African (AFR) AF: 0.000337 AC: 14 AN: 41564

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0266 AC: 138 AN: 5186

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.00157

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Brugada syndrome 5 (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	2.6
DANN	Benign	0.83
PhyloP100		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs3746255; hg19: chr19-35524546; COSMIC: COSV52896040; COSMIC: COSV52896040;