rs771117930

Variant names:

• chr2-165154502-C-T
• rs771117930
• NM_006922.4:c.1330G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-165154502-C-T
• chr2-165154502-C-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006922.4(SCN3A):​c.1330G>A​(p.Glu444Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SCN3A NM_006922.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91
• Publications: 3 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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828
• BS2: High AC in GnomAdExome4 at 9 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.1330G>A	p.Glu444Lys	missense	Exon 11 of 28	NP_008853.3
	SCN3A	NM_001081676.2		c.1330G>A	p.Glu444Lys	missense	Exon 11 of 28	NP_001075145.1	Q9NY46-4
	SCN3A	NM_001081677.2		c.1330G>A	p.Glu444Lys	missense	Exon 11 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.1330G>A	p.Glu444Lys	missense	Exon 11 of 28	ENSP00000283254.7	Q9NY46-3
	SCN3A	ENST00000409101.7	TSL:1	c.1330G>A	p.Glu444Lys	missense	Exon 11 of 28	ENSP00000386726.3	Q9NY46-2
	SCN3A	ENST00000706067.1		c.1330G>A	p.Glu444Lys	missense	Exon 11 of 28	ENSP00000516211.1	A0A994J5P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251442 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.020	D
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.49		Gain of ubiquitination at E444 (P = 0.0039)
MVP		0.90
MPC		1.3
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.25
gMVP		0.92
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs771117930; hg19: chr2-166011012; COSMIC: COSV51807783;