chr19-35030858-T-C

Variant names:

• chr19-35030858-T-C
• rs786205834
• NM_001037.5:c.38T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001037.5(SCN1B):​c.38T>C​(p.Leu13Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 870,084 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L13L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense, splice_region
• Scores: Splicing: ADA: 0.0004213
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: -0.0190
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.38T>C	p.Leu13Pro	missense splice_region	Exon 1 of 6	NP_001028.1	Q07699-1
	SCN1B	NM_199037.5		c.38T>C	p.Leu13Pro	missense splice_region	Exon 1 of 3	NP_950238.1	Q07699-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.38T>C	p.Leu13Pro	missense splice_region	Exon 1 of 6	ENSP00000262631.3	Q07699-1
	SCN1B	ENST00000415950.5	TSL:1	c.38T>C	p.Leu13Pro	missense splice_region	Exon 1 of 3	ENSP00000396915.2	Q07699-2
	SCN1B	ENST00000638536.1	TSL:1	c.38T>C	p.Leu13Pro	missense splice_region	Exon 1 of 5	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes AF: 0.00000671 AC: 1 AN: 149058 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 2 AN: 721026 Hom.: 0 Cov.: 10 AF XY: 0.00000290 AC XY: 1 AN XY: 344252

African (AFR) AF: 0.00 AC: 0 AN: 13964

American (AMR) AF: 0.00 AC: 0 AN: 3890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7238

East Asian (EAS) AF: 0.00 AC: 0 AN: 11058

South Asian (SAS) AF: 0.0000619 AC: 1 AN: 16146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1724

European-Non Finnish (NFE) AF: 0.00000159 AC: 1 AN: 627394

Other (OTH) AF: 0.00 AC: 0 AN: 26554

GnomAD4 genome AF: 0.00000671 AC: 1 AN: 149058 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72690

African (AFR) AF: 0.00 AC: 0 AN: 40914

American (AMR) AF: 0.00 AC: 0 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 5044

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66916

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not specified (3)
-	1	-	Brugada syndrome 5 (1)
-	1	-	Cardiovascular phenotype (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)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.0	N
PhyloP100		-0.019
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.023	D
Sift4G	Benign	0.073	T
Polyphen		0.84	P
Vest4		0.41
MutPred		0.72		Gain of loop (P = 0.0195)
MVP		0.96
MPC		1.1
ClinPred		0.25	T
GERP RS		3.2
PromoterAI		-0.036	Neutral
Varity_R		0.76
gMVP		0.87
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.020
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: rs786205834; hg19: chr19-35521762;