chr2-165992367-TC-CT

Variant names:

• chr2-165992367-TC-CT
• NM_001165963.4:c.4907_4908delGAinsAG
• SCN1A p.Arg1636Gln

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_ModerateO7_SupportingO8_Supporting

The NM_001165963.4(SCN1A):c.4907_4908delGAinsAG (p.Arg1636Gln) 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: 7.77). 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.R1636G: Likely_pathogenic (ClinVar VariationId 2031256, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1636= (synonymous): Likely_benign (ClinVar VariationId 951192, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• Publications: 0 publications found

Genes affected

SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]

SCN1A Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 6A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Dravet syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, ClinGen
• generalized epilepsy with febrile seizures plus, type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• migraine, familial hemiplegic, 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• arthrogryposis

  Inheritance: AD Classification: MODERATE Submitted by: Franklin by Genoox
• familial hemiplegic migraine

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

SCN1A-AS1 (HGNC:54069): ()

LOC102724058 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for SCN1A 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])
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 17 pathogenic, 0 benign (OR vs. background: 175.0); Variant does not impact splicing — splice-hotspot path not applicable
	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: 7.62 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001165963.4. 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
	SCN1A NM_001165963.4	MANE Select	c.4907_4908delGAinsAG p.Arg1636Gln	missense	N/A	Prot: NP_001159435.1 UniProt:
	SCN1A NM_001202435.3		c.4907_4908delGAinsAG p.Arg1636Gln	missense	N/A	Prot: NP_001189364.1 UniProt:
	SCN1A NM_001353948.2		c.4907_4908delGAinsAG p.Arg1636Gln	missense	N/A	Prot: NP_001340877.1 UniProt:

SCN1A NM_001165963.4

MANE Select

HGVSc / HGVSpc.4907_4908delGAinsAGp.Arg1636Gln

Exon rankN/A

missense

Prot: NP_001159435.1UniProt: P35498-1

SCN1A NM_001202435.3

HGVSc / HGVSpc.4907_4908delGAinsAGp.Arg1636Gln

Exon rankN/A

missense

Prot: NP_001189364.1UniProt: P35498-1

SCN1A NM_001353948.2

HGVSc / HGVSpc.4907_4908delGAinsAGp.Arg1636Gln

Exon rankN/A

missense

Prot: NP_001340877.1UniProt: P35498-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SCN1A ENST00000674923.1	MANE Select	c.4907_4908delGAinsAG p.Arg1636Gln	missense	N/A	Prot: ENSP00000501589.1 UniProt:
	SCN1A ENST00000303395.9	TSL:5	c.4907_4908delGAinsAG p.Arg1636Gln	missense	N/A	Prot: ENSP00000303540.4 UniProt:
	SCN1A ENST00000375405.7	TSL:5	c.4874_4875delGAinsAG p.Arg1625Gln	missense	N/A	Prot: ENSP00000364554.3 UniProt:

SCN1A ENST00000674923.1

MANE Select

HGVSc / HGVSpc.4907_4908delGAinsAGp.Arg1636Gln

Exon rankN/A

missense

Prot: ENSP00000501589.1UniProt: P35498-1

SCN1A ENST00000303395.9

TSL:5

HGVSc / HGVSpc.4907_4908delGAinsAGp.Arg1636Gln

Exon rankN/A

missense

Prot: ENSP00000303540.4UniProt: P35498-1

SCN1A ENST00000375405.7

TSL:5

HGVSc / HGVSpc.4874_4875delGAinsAGp.Arg1625Gln

Exon rankN/A

missense

Prot: ENSP00000364554.3UniProt: P35498-2

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	7.8

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: chr2-166848877;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar