19-35030828-G-C

Position:

• chr19-35030828-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001037.5(SCN1B):​c.8G>C​(p.Arg3Thr) 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. 14/21 in silico tools predict a benign 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN1B NM_001037.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0240

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14800426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.8G>C	p.Arg3Thr	missense_variant	1/6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.8G>C	p.Arg3Thr	missense_variant	1/3		NP_950238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.8G>C	p.Arg3Thr	missense_variant	1/6	1	NM_001037.5	ENSP00000262631.3
SCN1B	ENST00000415950.5	c.8G>C	p.Arg3Thr	missense_variant	1/3	1		ENSP00000396915.2
SCN1B	ENST00000638536.1	c.8G>C	p.Arg3Thr	missense_variant	1/5	1		ENSP00000492022.1
SCN1B	ENST00000595652.5	c.8G>C	p.Arg3Thr	missense_variant	1/6	2		ENSP00000468848.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 938412 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 457982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.74
DEOGEN2	Benign	0.051	T;T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.45	.;T;T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Uncertain	-0.020	T
MutationAssessor	Benign	0.0	N;N;N;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.81	N;.;N;.
REVEL	Benign	0.22
Sift	Benign	0.58	T;.;T;.
Sift4G	Benign	0.48	T;.;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.13
MutPred		0.35		Loss of methylation at R3 (P = 0.0101);Loss of methylation at R3 (P = 0.0101);Loss of methylation at R3 (P = 0.0101);Loss of methylation at R3 (P = 0.0101);
MVP		0.89
MPC		0.98
ClinPred		0.027	T
GERP RS		0.0044
Varity_R		0.044
gMVP		0.54

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-35521732;