chr11-123634199-A-AG

Position:

• chr11-123634199-A-AG

Variant summary

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

The NM_001040151.2(SCN3B):​c.591_592insC​(p.Tyr198LeufsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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: SCN3B NM_001040151.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN3B	NM_001040151.2	c.591_592insC	p.Tyr198LeufsTer7	frameshift_variant	6/7	ENST00000299333.8
SCN3B	NM_018400.4	c.591_592insC	p.Tyr198LeufsTer7	frameshift_variant	5/6
SCN3B	XM_011542897.3	c.591_592insC	p.Tyr198LeufsTer7	frameshift_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN3B	ENST00000299333.8	c.591_592insC	p.Tyr198LeufsTer7	frameshift_variant	6/7	1	NM_001040151.2	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2017

The c.591dupC variant, located in coding exon 5 of the SCN3B gene, results from a duplication of one nucleotide at position 591, causing a translational frameshift with a predicted alternate stop codon (p.Y198Lfs*7). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of SCN3B, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 18 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. Additionally, loss of function of SCN3B has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1555114543; hg19: chr11-123504907;