rs121918738

Variant names:

• chr2-166013820-G-A
• rs121918738
• NM_001165963.4:c.3629C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166013820-G-A
• chr2-166013820-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3_Moderate PS4 PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001165963.4(SCN1A):c.3629C>T is a missense variant predicted to cause substitution of threonine by methionine at amino acid 1210 (p.Thr1210Met). The variant has been identified in two probands with consistent phenotypes (Genetic epilepsy with febrile seizures plus) in published literature (PMID:35074891 and PMID:28202706)(PS4). One proband inherited the variant from an unaffected father (PMID:28202706). Another missense variant at the same amino acid position in SCN1A (c.3629C>A, p.Thr1210Lys) has been classified as likely pathogenic for a consistent phenotype (Dravet syndrome)(PM5_supporting). The allele frequency for the variant is 0.002% with 4 alleles in gnomAD V2.1.1 (PM2_supporting and BS1 are not met). The computational predictor REVEL gives a score of 0.841, which is above the threshold of 0.773, evidence that correlates with a maximum strength of PP3_Moderate. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant Genetic epilepsy with febrile seizures plus on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PS4, PM5_supporting, PP3_Moderate. (version 1.0; March 26, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1942910/MONDO:0018214/067

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 9.99
• Publications: 11 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)

LOC102724058 (HGNC:):

ACMG classification

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

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.3629C>T	p.Thr1210Met	missense	Exon 21 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.3629C>T	p.Thr1210Met	missense	Exon 20 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.3629C>T	p.Thr1210Met	missense	Exon 19 of 27	NP_001340877.1	P35498-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.3629C>T	p.Thr1210Met	missense	Exon 21 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.3629C>T	p.Thr1210Met	missense	Exon 20 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.3596C>T	p.Thr1199Met	missense	Exon 18 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151610 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250842 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460526 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726580

African (AFR) AF: 0.0000299 AC: 1 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110978

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151610 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74038

African (AFR) AF: 0.0000483 AC: 2 AN: 41370

American (AMR) AF: 0.00 AC: 0 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67694

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00000449 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy (1)
1	-	-	Generalized epilepsy with febrile seizures plus (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		10
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.88
gMVP		0.88
Mutation Taster		=1/99	disease causing

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: rs121918738; hg19: chr2-166870330; COSMIC: COSV57675473; COSMIC: COSV57675473;