Genetic Variant SCN3A:p.Leu1356Phe (chr2-165097423-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006922.4(SCN3A):c.4068G>C(p.Leu1356Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1356L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SCN3A
NM_006922.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.966

Publications

0 publications found

Variant links:

Genes affected

SCN3A (HGNC:10590): (sodium voltage-gated channel alpha subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains 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 alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SCN3A Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
developmental and epileptic encephalopathy, 62
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
epilepsy, familial focal, with variable foci 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SCN3A links:

ENSG00000236283 (HGNC:):

ENSG00000236283 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006922.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN3A	NM_006922.4	MANE Select	c.4068G>C	p.Leu1356Phe	missense	Exon 23 of 28	NP_008853.3
SCN3A	NM_001081676.2		c.3921G>C	p.Leu1307Phe	missense	Exon 23 of 28	NP_001075145.1
SCN3A	NM_001081677.2		c.3921G>C	p.Leu1307Phe	missense	Exon 23 of 28	NP_001075146.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN3A	ENST00000283254.12	TSL:1 MANE Select	c.4068G>C	p.Leu1356Phe	missense	Exon 23 of 28	ENSP00000283254.7
SCN3A	ENST00000409101.7	TSL:1	c.3921G>C	p.Leu1307Phe	missense	Exon 23 of 28	ENSP00000386726.3
SCN3A	ENST00000706067.1		c.4017G>C	p.Leu1339Phe	missense	Exon 23 of 28	ENSP00000516211.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.8

PhyloP100

0.97

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.82

Sift

Benign

0.034

Sift4G

Benign

0.21

Polyphen

0.97

Vest4

0.84

MutPred

0.73

Loss of sheet (P = 0.0228)

MVP

0.95

MPC

1.8

ClinPred

0.98

GERP RS

3.9

Varity_R

0.29

gMVP

0.99

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over