chr19-35030858-T-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001037.5(SCN1B):​c.38T>A​(p.Leu13Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 721,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L13P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense, splice_region
• Scores: Splicing: ADA: 0.0002501
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0190
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40847212).

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.38T>A	p.Leu13Gln	missense splice_region	Exon 1 of 6	NP_001028.1
	SCN1B	NM_199037.5		c.38T>A	p.Leu13Gln	missense splice_region	Exon 1 of 3	NP_950238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.38T>A	p.Leu13Gln	missense splice_region	Exon 1 of 6	ENSP00000262631.3
	SCN1B	ENST00000415950.5	TSL:1	c.38T>A	p.Leu13Gln	missense splice_region	Exon 1 of 3	ENSP00000396915.2
	SCN1B	ENST00000638536.1	TSL:1	c.38T>A	p.Leu13Gln	missense splice_region	Exon 1 of 5	ENSP00000492022.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000139 AC: 1 AN: 721024 Hom.: 0 Cov.: 10 AF XY: 0.00000290 AC XY: 1 AN XY: 344252

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00 AC: 0 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: 627392

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	0.0	N
PhyloP100		-0.019
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.70
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.84	P
Vest4		0.52
MutPred		0.52		Gain of loop (P = 0.0195)
MVP		0.96
MPC		0.70
ClinPred		0.23	T
GERP RS		3.2
PromoterAI		0.0052	Neutral
Varity_R		0.31
gMVP		0.79
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.0080
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;