2-165992368-C-A

Variant names:

• chr2-165992368-C-A
• rs121917995
• NM_001165963.4:c.4907G>T
• SCN1A p.Arg1636Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACMG Germline Pathogenicity v2019). PM1PM2_SupportingPM5PP2PP3PP5_Moderate

The NM_001165963.4(SCN1A):c.4907G>T (p.Arg1636Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,640 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000252. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.77). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★). 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)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.77
• Publications: 13 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 ACMG Germline Pathogenicity v2019

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: Likely_pathogenic. The variant received 9 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: 17 pathogenic, 0 benign (OR vs. background: 175.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000252 — borderline rare for AD/XL gene (base 0.0001, raised to 0.000138 by highest known P/LP ClinVar AF 0.000138) — PM2 supporting.
	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.R1636G: Likely_pathogenic (ClinVar VariationId 2031256, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R1636= (synonymous): Likely_benign (ClinVar VariationId 951192, 2 stars)
	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: 7.618). ClinVar shows strong pathogenic missense enrichment: 1210 P/LP and 153 B/LB missense entries (ratio 7.9×).
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — supporting computational evidence (PP3); Splicing verdict: pathogenic (Supporting).; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

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.4907G>T p.Arg1636Leu	missense	Exon 29 of 29	Prot: NP_001159435.1 UniProt:
	SCN1A NM_001202435.3		c.4907G>T p.Arg1636Leu	missense	Exon 28 of 28	Prot: NP_001189364.1 UniProt:
	SCN1A NM_001353948.2		c.4907G>T p.Arg1636Leu	missense	Exon 27 of 27	Prot: NP_001340877.1 UniProt:

SCN1A NM_001165963.4

MANE Select

HGVSc / HGVSpc.4907G>Tp.Arg1636Leu

Exon rankExon 29 of 29

missense

Prot: NP_001159435.1UniProt: P35498-1

SCN1A NM_001202435.3

HGVSc / HGVSpc.4907G>Tp.Arg1636Leu

Exon rankExon 28 of 28

missense

Prot: NP_001189364.1UniProt: P35498-1

SCN1A NM_001353948.2

HGVSc / HGVSpc.4907G>Tp.Arg1636Leu

Exon rankExon 27 of 27

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.4907G>T p.Arg1636Leu	missense	Exon 29 of 29	Prot: ENSP00000501589.1 UniProt:
	SCN1A ENST00000303395.9	TSL:5	c.4907G>T p.Arg1636Leu	missense	Exon 28 of 28	Prot: ENSP00000303540.4 UniProt:
	SCN1A ENST00000375405.7	TSL:5	c.4874G>T p.Arg1625Leu	missense	Exon 26 of 26	Prot: ENSP00000364554.3 UniProt:

SCN1A ENST00000674923.1

MANE Select

HGVSc / HGVSpc.4907G>Tp.Arg1636Leu

Exon rankExon 29 of 29

missense

Prot: ENSP00000501589.1UniProt: P35498-1

SCN1A ENST00000303395.9

TSL:5

HGVSc / HGVSpc.4907G>Tp.Arg1636Leu

Exon rankExon 28 of 28

missense

Prot: ENSP00000303540.4UniProt: P35498-1

SCN1A ENST00000375405.7

TSL:5

HGVSc / HGVSpc.4874G>Tp.Arg1625Leu

Exon rankExon 26 of 26

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461640	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	67866	0.00000750	1	133312

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Early-infantile DEE (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	33
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
FuncVEP CTI	Pathogenic	0.95
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	1/99	disease causing
MutationAssessor	Pathogenic	3.6	H
PhyloP100	Pathogenic	7.8
popEVE	Pathogenic	-5.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.56
VESM-3B	Benign	-16

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_AG_spliceai	Pathogenic	0.60	Position offset: -3
Pangolin (max)	Benign	0.12
Pangolin gain	Benign	0.12	Position offset: -3
SpliceAI score (max)	Pathogenic	0.60	Details are displayed if max score is > 0.2

Showing 4 of 4 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: rs121917995;

hg19: chr2-166848878;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar