19-35039258-C-G

Variant names:

• chr19-35039258-C-G
• rs554201948
• NM_001037.5:c.590C>G

Variant summary

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

The NM_001037.5(SCN1B):​c.590C>G​(p.Ala197Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,434 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A197V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN1B NM_001037.5 missense, splice_region
• Scores: Splicing: ADA: 0.2797
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50
• 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 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.590C>G	p.Ala197Gly	missense splice_region	Exon 4 of 6	NP_001028.1	Q07699-1
	SCN1B	NM_001321605.2		c.491C>G	p.Ala164Gly	missense splice_region	Exon 4 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.590C>G	p.Ala197Gly	missense splice_region	Exon 4 of 6	ENSP00000262631.3	Q07699-1
	SCN1B	ENST00000638536.1	TSL:1	c.590C>G	p.Ala197Gly	missense splice_region	Exon 4 of 5	ENSP00000492022.1	Q07699-1
	SCN1B	ENST00000675741.1		c.617C>G	p.Ala206Gly	missense splice_region	Exon 4 of 6	ENSP00000502395.1	A0A6Q8PGS1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460434 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726568

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.5
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.58
Sift	Benign	0.046	D
Sift4G	Uncertain	0.026	D
Polyphen		0.95	P
Vest4		0.50
MutPred		0.38		Gain of sheet (P = 0.0011)
MVP		0.98
ClinPred		0.85	D
GERP RS		4.1
Varity_R		0.20
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.28
dbscSNV1_RF	Benign	0.53
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: rs554201948; hg19: chr19-35530162;