19-35030821-A-G

Variant names:

• chr19-35030821-A-G
• rs1375857363
• NM_001037.5:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001037.5(SCN1B):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 927,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SCN1B NM_001037.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.694
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 34 codons. Genomic position: 35032587. Lost 0.152 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.1A>G	p.Met1?	start_lost	Exon 1 of 3		NP_950238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000216 AC: 2 AN: 927682 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 453832

⚠️ 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: 17164

American (AMR) AF: 0.00 AC: 0 AN: 7050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10172

East Asian (EAS) AF: 0.00 AC: 0 AN: 13116

South Asian (SAS) AF: 0.00 AC: 0 AN: 40532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2284

European-Non Finnish (NFE) AF: 0.00000255 AC: 2 AN: 785768

Other (OTH) AF: 0.00 AC: 0 AN: 33786

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Benign	0.75
DEOGEN2	Benign	0.12	T;T;.;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.16	D
PhyloP100		0.69
PROVEAN	Benign	-1.2	N;.;N;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.027	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		0.0030	B;B;B;B
Vest4		0.25
MutPred		0.89		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.85
ClinPred		0.45	T
GERP RS		0.26
PromoterAI		-0.20	Neutral
Varity_R		0.41
gMVP		0.87
Mutation Taster		=10/190	disease causing

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: rs1375857363; hg19: chr19-35521725;