chr19-35039191-G-T

Variant names:

• chr19-35039191-G-T
• rs776213428
• NM_001037.5:c.523G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001037.5(SCN1B):​c.523G>T​(p.Val175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V175M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02
• Publications: 3 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.523G>T	p.Val175Leu	missense	Exon 4 of 6	NP_001028.1
	SCN1B	NM_001321605.2		c.424G>T	p.Val142Leu	missense	Exon 4 of 6	NP_001308534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.523G>T	p.Val175Leu	missense	Exon 4 of 6	ENSP00000262631.3
	SCN1B	ENST00000638536.1	TSL:1	c.523G>T	p.Val175Leu	missense	Exon 4 of 5	ENSP00000492022.1
	SCN1B	ENST00000675741.1		c.550G>T	p.Val184Leu	missense	Exon 4 of 6	ENSP00000502395.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.060	N
PhyloP100		2.0
PROVEAN	Benign	0.43	N
REVEL	Uncertain	0.36
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.39		Gain of sheet (P = 0.0827)
MVP		0.84
ClinPred		0.30	T
GERP RS		4.1
Varity_R		0.15
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776213428; hg19: chr19-35530095;