chr2-165309227-G-T

Variant names:

• chr2-165309227-G-T
• rs1553567488
• NM_001371246.1:c.668G>T
• SCN2A p.Arg223Ile

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_SupportingO8_Supporting

The NM_001371246.1(SCN2A):c.668G>T (p.Arg223Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The gene SCN2A is a tumor suppressor gene (CancerMine: 1 TSG citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN2A NM_001371246.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SCN2A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, PanelApp Australia, ClinGen
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for SCN2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 8.73 (threshold ≥3.09 for constraint)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001371246.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN2A NM_001371246.1	MANE Plus Clinical	c.668G>T p.Arg223Ile	missense	Exon 6 of 27	Prot: NP_001358175.1 UniProt:
	SCN2A NM_001040142.2	MANE Select	c.606-125G>T	intron	Intron 5 of 26	Prot: NP_001035232.1 UniProt:
	SCN2A NM_001040143.2		c.668G>T p.Arg223Ile	missense	Exon 7 of 28	Prot: NP_001035233.1 UniProt:

SCN2A NM_001371246.1

MANE Plus Clinical

HGVSc / HGVSpc.668G>Tp.Arg223Ile

Exon rankExon 6 of 27

missense

Prot: NP_001358175.1UniProt: Q99250-2

SCN2A NM_001040142.2

MANE Select

HGVSc / HGVSpc.606-125G>T

Exon rankIntron 5 of 26

intron

Prot: NP_001035232.1UniProt: Q99250-1

SCN2A NM_001040143.2

HGVSc / HGVSpc.668G>Tp.Arg223Ile

Exon rankExon 7 of 28

missense

Prot: NP_001035233.1UniProt: Q99250-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN2A ENST00000631182.3	TSL:5MANE Plus Clinical	c.668G>T p.Arg223Ile	missense	Exon 6 of 27	Prot: ENSP00000486885.1 UniProt:
	SCN2A ENST00000375437.7	TSL:5MANE Select	c.606-125G>T	intron	Intron 5 of 26	Prot: ENSP00000364586.2 UniProt:
	SCN2A ENST00000283256.10	TSL:1	c.606-125G>T	intron	Intron 5 of 26	Prot: ENSP00000283256.6 UniProt:

SCN2A ENST00000631182.3

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.668G>Tp.Arg223Ile

Exon rankExon 6 of 27

missense

Prot: ENSP00000486885.1UniProt: Q99250-2

SCN2A ENST00000375437.7

TSL:5MANE Select

HGVSc / HGVSpc.606-125G>T

Exon rankIntron 5 of 26

intron

Prot: ENSP00000364586.2UniProt: Q99250-1

SCN2A ENST00000283256.10

TSL:1

HGVSc / HGVSpc.606-125G>T

Exon rankIntron 5 of 26

intron

Prot: ENSP00000283256.6UniProt: Q99250-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	33
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-9.9
GPN-Star score	N/A	9.9
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	1/99	disease causing
PhyloP100	Pathogenic	10
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
VESM-3B	Benign	-17

Showing 23 of 23 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_DL_spliceai	Uncertain	0.26	Position offset: 29
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Uncertain	0.26	Details are displayed if max score is > 0.2

Showing 3 of 3 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1553567488;

hg19: chr2-166165737;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar