11-118166937-C-T

Variant names:

• chr11-118166937-C-T
• rs1485320329
• NM_004588.5:c.598G>A

Variant summary

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

The NM_004588.5(SCN2B):​c.598G>A​(p.Glu200Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2B NM_004588.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.58

Genes affected

SCN2B (HGNC:10589): (sodium voltage-gated channel beta subunit 2) The protein encoded by this gene is the beta 2 subunit of the type II voltage-gated sodium channel. The encoded protein is involved in cell-cell adhesion and cell migration. Defects in this gene can be a cause of Brugada Syndrome, atrial fibrillation, or sudden infant death syndrome. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2B	NM_004588.5	c.598G>A	p.Glu200Lys	missense_variant	Exon 4 of 4	ENST00000278947.6	NP_004579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2B	ENST00000278947.6	c.598G>A	p.Glu200Lys	missense_variant	Exon 4 of 4	1	NM_004588.5	ENSP00000278947.5
SCN2B	ENST00000658882.1	n.*423G>A		non_coding_transcript_exon_variant	Exon 5 of 5			ENSP00000499572.1
SCN2B	ENST00000669850.1	n.840G>A		non_coding_transcript_exon_variant	Exon 4 of 4
SCN2B	ENST00000658882.1	n.*423G>A		3_prime_UTR_variant	Exon 5 of 5			ENSP00000499572.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Aug 31, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E200K variant (also known as c.598G>A), located in coding exon 4 of the SCN2B gene, results from a G to A substitution at nucleotide position 598. The glutamic acid at codon 200 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.51
MutPred		0.14		Gain of ubiquitination at E200 (P = 0.0094);
MVP		0.85
MPC		0.92
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.49
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs1485320329; hg19: chr11-118037652; COSMIC: COSV54050190;