chr11-123634177-T-C

Variant names:

• chr11-123634177-T-C
• rs781244975
• NM_001040151.2:c.614A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001040151.2(SCN3B):​c.614A>G​(p.Asn205Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN3B NM_001040151.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.60

Genes affected

SCN3B (HGNC:20665): (sodium voltage-gated channel beta subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel beta subunit gene family, and influences the inactivation kinetics of the sodium channel. Two alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2557812).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN3B	NM_001040151.2	c.614A>G	p.Asn205Ser	missense_variant	Exon 6 of 7	ENST00000299333.8	NP_001035241.1
SCN3B	NM_018400.4	c.614A>G	p.Asn205Ser	missense_variant	Exon 5 of 6		NP_060870.1
SCN3B	XM_011542897.3	c.614A>G	p.Asn205Ser	missense_variant	Exon 6 of 7		XP_011541199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN3B	ENST00000299333.8	c.614A>G	p.Asn205Ser	missense_variant	Exon 6 of 7	1	NM_001040151.2	ENSP00000299333.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251398 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727142

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Mar 25, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

Mar 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N205S variant (also known as c.614A>G), located in coding exon 5 of the SCN3B gene, results from an A to G substitution at nucleotide position 614. The asparagine at codon 205 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Brugada syndrome 7 Uncertain:1

Aug 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;.
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.045	N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.27	N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.92	T;T;T
Sift4G	Benign	0.94	T;T;T
Polyphen		0.90	P;P;P
Vest4		0.24
MutPred		0.13		Gain of phosphorylation at N205 (P = 0.023);Gain of phosphorylation at N205 (P = 0.023);Gain of phosphorylation at N205 (P = 0.023);
MVP		0.91
MPC		0.49
ClinPred		0.54	D
GERP RS		5.8
Varity_R		0.15
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs781244975; hg19: chr11-123504885;