rs121917995

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-165992368-C-A
• chr2-165992368-C-G
• chr2-165992368-C-T

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: 0 publications found

Genes affected

SCN1A (HGNC:10585): ()

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