chr2-165309413-CGA-ATC

Variant names:

• chr2-165309413-CGA-ATC
• NM_001040142.2:c.667_669delCGAinsATC
• SCN2A p.Arg223Ile

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+7 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 7 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP2

The NM_001040142.2(SCN2A):c.667_669delCGAinsATC (p.Arg223Ile) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R223L: Pathogenic (ClinVar VariationId 4532322, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R223= (synonymous): Uncertain_significance (ClinVar VariationId 4782767, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 ACMG Germline Pathogenicity v2019

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: Likely_pathogenic. The variant received 7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 11 pathogenic, 0 benign (OR vs. background: 115.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R223L: Pathogenic (ClinVar VariationId 4532322, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R223= (synonymous): Uncertain_significance (ClinVar VariationId 4782767, 1 star)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 8.727). ClinVar shows strong pathogenic missense enrichment: 465 P/LP and 76 B/LB missense entries (ratio 6.1×).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001040142.2. 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_001040142.2	MANE Select	c.667_669delCGAinsATC p.Arg223Ile	missense	N/A	Prot: NP_001035232.1 UniProt:
	SCN2A NM_001371246.1	MANE Plus Clinical	c.697+157_697+159delCGAinsATC	intron	Intron 6 of 26	Prot: NP_001358175.1 UniProt:
	SCN2A NM_001371247.1		c.667_669delCGAinsATC p.Arg223Ile	missense	N/A	Prot: NP_001358176.1 UniProt:

SCN2A NM_001040142.2

MANE Select

HGVSc / HGVSpc.667_669delCGAinsATCp.Arg223Ile

Exon rankN/A

missense

Prot: NP_001035232.1UniProt: Q99250-1

SCN2A NM_001371246.1

MANE Plus Clinical

HGVSc / HGVSpc.697+157_697+159delCGAinsATC

Exon rankIntron 6 of 26

intron

Prot: NP_001358175.1UniProt: Q99250-2

SCN2A NM_001371247.1

HGVSc / HGVSpc.667_669delCGAinsATCp.Arg223Ile

Exon rankN/A

missense

Prot: NP_001358176.1UniProt: Q99250-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN2A ENST00000375437.7	TSL:5MANE Select	c.667_669delCGAinsATC p.Arg223Ile	missense	N/A	Prot: ENSP00000364586.2 UniProt:
	SCN2A ENST00000283256.10	TSL:1	c.667_669delCGAinsATC p.Arg223Ile	missense	N/A	Prot: ENSP00000283256.6 UniProt:
	SCN2A ENST00000424833.5	TSL:1	c.667_669delCGAinsATC p.Arg223Ile	missense	N/A	Prot: ENSP00000406454.2 UniProt:

SCN2A ENST00000375437.7

TSL:5MANE Select

HGVSc / HGVSpc.667_669delCGAinsATCp.Arg223Ile

Exon rankN/A

missense

Prot: ENSP00000364586.2UniProt: Q99250-1

SCN2A ENST00000283256.10

TSL:1

HGVSc / HGVSpc.667_669delCGAinsATCp.Arg223Ile

Exon rankN/A

missense

Prot: ENSP00000283256.6UniProt: Q99250-1

SCN2A ENST00000424833.5

TSL:1

HGVSc / HGVSpc.667_669delCGAinsATCp.Arg223Ile

Exon rankN/A

missense

Prot: ENSP00000406454.2UniProt: F6U291

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	10

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr2-166165923;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar