2-165176351-C-A

Variant names:

• chr2-165176351-C-A
• rs139769668
• NM_006922.4:c.44G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006922.4(SCN3A):​c.44G>T​(p.Arg15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R15H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.524
• Publications: 11 publications found

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, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia
• 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

ENSG00000236283 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3A	NM_006922.4	MANE Select	c.44G>T	p.Arg15Leu	missense	Exon 3 of 28	NP_008853.3
	SCN3A	NM_001081676.2		c.44G>T	p.Arg15Leu	missense	Exon 3 of 28	NP_001075145.1	Q9NY46-4
	SCN3A	NM_001081677.2		c.44G>T	p.Arg15Leu	missense	Exon 3 of 28	NP_001075146.1	Q9NY46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3A	ENST00000283254.12	TSL:1 MANE Select	c.44G>T	p.Arg15Leu	missense	Exon 3 of 28	ENSP00000283254.7	Q9NY46-3
	SCN3A	ENST00000409101.7	TSL:1	c.44G>T	p.Arg15Leu	missense	Exon 3 of 28	ENSP00000386726.3	Q9NY46-2
	SCN3A	ENST00000706067.1		c.44G>T	p.Arg15Leu	missense	Exon 3 of 28	ENSP00000516211.1	A0A994J5P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251228 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		0.52
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.032	D
Polyphen		0.63	P
Vest4		0.59
MutPred		0.49		Loss of MoRF binding (P = 0.0186)
MVP		0.75
MPC		1.4
ClinPred		0.87	D
GERP RS		4.5
Varity_R		0.17
gMVP		0.68
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs139769668; hg19: chr2-166032861;