rs794726766

Variant names:

• chr2-166041343-G-A
• rs794726766
• NM_001165963.4:c.2303C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PP3_Moderate PS4_Moderate PM6

This summary comes from the ClinGen Evidence Repository: The c.2303C>T (NM_001165963.4) variant in SCN1A is a missense variant predicted to cause substitution of proline by leucine at amino acid 768 (p.Pro768Leu). This variant has been reported in one patient meeting phenotypic criteria for Dravet syndrome with unknown inheritance (PMID:35074891; PS4_SUPPORTING) and in another patient also meeting phenotypic criteria for Dravet syndrome as a de novo occurrence with unconfirmed parental relationships (PMID:20431604; PM6). This variant is absent from gnomAD v2 and v3 (PM2_SUPPORTING). The computational predictor REVEL gives a score of 0.927 which is above the threshold of 0.773 but under 0.932, evidence that correlates with impact to SCN1A function (PMID:36413997; PP3_MODERATE). In summary, this variant has been classified as likely pathogenic for autosomal dominant Dravet syndrome based on the ACMG/AMP criteria applied, as specified by the Epilepsy Sodium Channel VCEP: PM6, PS4_SUPPORTING, PM2_SUPPORTING, PP3_MODERATE (version 1.0, approved 7/11/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA303333/MONDO:0100135/067

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 10.0
• Publications: 2 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-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.2303C>T	p.Pro768Leu	missense	Exon 16 of 29	NP_001159435.1
	SCN1A	NM_001202435.3		c.2303C>T	p.Pro768Leu	missense	Exon 15 of 28	NP_001189364.1
	SCN1A	NM_001353948.2		c.2303C>T	p.Pro768Leu	missense	Exon 14 of 27	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.2303C>T	p.Pro768Leu	missense	Exon 16 of 29	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.2303C>T	p.Pro768Leu	missense	Exon 15 of 28	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.2270C>T	p.Pro757Leu	missense	Exon 13 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
2	-	-	Severe myoclonic epilepsy in infancy (2)
1	-	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		10
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.84
MutPred		0.58		Loss of sheet (P = 0.0457)
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs794726766; hg19: chr2-166897853;