11-123634163-C-T

Variant summary

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

The NM_001040151.2(SCN3B):c.628G>A(p.Ala210Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. A210V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN3B NM_001040151.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

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 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=0.13046324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN3B	NM_001040151.2	c.628G>A	p.Ala210Thr	missense_variant	6/7	ENST00000299333.8
SCN3B	NM_018400.4	c.628G>A	p.Ala210Thr	missense_variant	5/6
SCN3B	XM_011542897.3	c.628G>A	p.Ala210Thr	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN3B	ENST00000299333.8	c.628G>A	p.Ala210Thr	missense_variant	6/7	1	NM_001040151.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000299

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2022

The p.A210T variant (also known as c.628G>A), located in coding exon 5 of the SCN3B gene, results from a G to A substitution at nucleotide position 628. The alanine at codon 210 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Benign	0.75	N;N;N
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.60	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.068	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.041	B;B;B
Vest4		0.27
MutPred		0.17		Gain of glycosylation at A210 (P = 0.0035);Gain of glycosylation at A210 (P = 0.0035);Gain of glycosylation at A210 (P = 0.0035);
MVP		0.87
MPC		0.45
ClinPred		0.45	T
GERP RS		5.8
Varity_R		0.093
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr11-123504871; COSMIC: COSV100173835;