NM_001040151.2:c.217C>A

Variant names:

• chr11-123645589-G-T
• rs786205425
• NM_001040151.2:c.217C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001040151.2(SCN3B):​c.217C>A​(p.Leu73Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN3B NM_001040151.2 missense, splice_region
• Scores: Splicing: ADA: 0.9398
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.36
• Publications: 0 publications found

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]

SCN3B Gene-Disease associations (from GenCC):

• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome 7

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36702913).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040151.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3B	NM_001040151.2	MANE Select	c.217C>A	p.Leu73Ile	missense splice_region	Exon 3 of 7	NP_001035241.1
	SCN3B	NM_018400.4		c.217C>A	p.Leu73Ile	missense splice_region	Exon 2 of 6	NP_060870.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3B	ENST00000299333.8	TSL:1 MANE Select	c.217C>A	p.Leu73Ile	missense splice_region	Exon 3 of 7	ENSP00000299333.3
	SCN3B	ENST00000392770.6	TSL:1	c.217C>A	p.Leu73Ile	missense splice_region	Exon 2 of 6	ENSP00000376523.2
	SCN3B	ENST00000530277.5	TSL:1	c.217C>A	p.Leu73Ile	missense splice_region	Exon 3 of 6	ENSP00000432785.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.3	L
PhyloP100		8.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.16
Sift	Benign	0.24	T
Sift4G	Benign	0.34	T
Polyphen		0.59	P
Vest4		0.45
MutPred		0.49		Gain of methylation at K70 (P = 0.0568)
MVP		0.54
MPC		0.85
ClinPred		0.90	D
GERP RS		6.0
Varity_R		0.23
gMVP		0.34
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.80
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

Other links and lift over

dbSNP: rs786205425; hg19: chr11-123516297;