rs72558029

Variant names:

• chr19-35033703-G-A
• rs72558029
• NM_001037.5:c.412G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-35033703-G-A
• chr19-35033703-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001037.5(SCN1B):​c.412G>A​(p.Val138Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,154 control chromosomes in the GnomAD database, including 367 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V138V) has been classified as Likely benign. The gene SCN1B is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0034 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (341 hom.)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.94
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017569363).
• BP6: Variant 19-35033703-G-A is Benign according to our data. Variant chr19-35033703-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 180508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0813 is higher than 0.05.

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.412G>A	p.Val138Ile	missense	Exon 3 of 6	NP_001028.1	Q07699-1
	SCN1B	NM_199037.5		c.412G>A	p.Val138Ile	missense	Exon 3 of 3	NP_950238.1	Q07699-2
	SCN1B	NM_001321605.2		c.313G>A	p.Val105Ile	missense	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.412G>A	p.Val138Ile	missense	Exon 3 of 6	ENSP00000262631.3	Q07699-1
	SCN1B	ENST00000415950.5	TSL:1	c.412G>A	p.Val138Ile	missense	Exon 3 of 3	ENSP00000396915.2	Q07699-2
	SCN1B	ENST00000638536.1	TSL:1	c.412G>A	p.Val138Ile	missense	Exon 3 of 5	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 518 AN: 152146 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.0877

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.0103 AC: 2601 AN: 251490 AF XY: 0.0136

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00586

GnomAD4 exome AF: 0.00517 AC: 7554 AN: 1461890 Hom.: 341 Cov.: 33 AF XY: 0.00725 AC XY: 5272 AN XY: 727244

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

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

East Asian (EAS) AF: 0.00297 AC: 118 AN: 39700

South Asian (SAS) AF: 0.0784 AC: 6763 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0000845 AC: 94 AN: 1112012

Other (OTH) AF: 0.00861 AC: 520 AN: 60396

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152264 Hom.: 26 Cov.: 32 AF XY: 0.00492 AC XY: 366 AN XY: 74440

African (AFR) AF: 0.000914 AC: 38 AN: 41554

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00851 AC: 44 AN: 5172

South Asian (SAS) AF: 0.0882 AC: 424 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00105 Hom.: 9

Bravo AF: 0.00109

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0117 AC: 1418

Asia WGS AF: 0.0550 AC: 189 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	4	not specified (4)
-	-	2	Brugada syndrome 5 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 1 (1)
-	-	1	Long QT syndrome (1)
-	-	1	SCN1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.052
Eigen_PC	Benign	0.065
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0018	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.45	N
PhyloP100		2.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.26
Sift	Benign	0.40	T
Sift4G	Benign	0.64	T
Polyphen		0.28	B
Vest4		0.041
MPC		0.71
ClinPred		0.0067	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.69
Mutation Taster		=95/5	polymorphism (auto)

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: rs72558029; hg19: chr19-35524607;