chr2-165998121-T-C

Variant names:

• chr2-165998121-T-C
• rs138231868
• NM_001165963.4:c.4393A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: This is a missense variant in SCN1A, c.4393A>G, (p.Ile1465Val). This variant is present in gnomAD at 0.04% within the total population, with the highest sub-population frequency of 0.4% within the African/African population American population (BA1). In summary, this variant meets criteria to be classified as benign for autosomal dominant dravet syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1 (version 1.0; approved 6/13/23). LINK:https://erepo.genome.network/evrepo/ui/classification/CA295639/MONDO:0100135/067

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 4.85
• Publications: 5 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: Benign. The variant received -8 ACMG points.

• BA1: 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.4393A>G	p.Ile1465Val	missense	Exon 26 of 29	NP_001159435.1
	SCN1A	NM_001202435.3		c.4393A>G	p.Ile1465Val	missense	Exon 25 of 28	NP_001189364.1
	SCN1A	NM_001353948.2		c.4393A>G	p.Ile1465Val	missense	Exon 24 of 27	NP_001340877.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.4393A>G	p.Ile1465Val	missense	Exon 26 of 29	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.4393A>G	p.Ile1465Val	missense	Exon 25 of 28	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.4360A>G	p.Ile1454Val	missense	Exon 23 of 26	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 167 AN: 151022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000273 AC: 68 AN: 249444 AF XY: 0.000222

Gnomad AFR exome AF: 0.00385

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 164 AN: 1454830 Hom.: 0 Cov.: 29 AF XY: 0.0000967 AC XY: 70 AN XY: 723888

African (AFR) AF: 0.00455 AC: 151 AN: 33196

American (AMR) AF: 0.000112 AC: 5 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.00 AC: 0 AN: 85840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107054

Other (OTH) AF: 0.000133 AC: 8 AN: 59996

GnomAD4 genome AF: 0.00110 AC: 167 AN: 151140 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 81 AN XY: 73816

African (AFR) AF: 0.00396 AC: 164 AN: 41402

American (AMR) AF: 0.000132 AC: 2 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67342

Other (OTH) AF: 0.00 AC: 0 AN: 2098

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.00125

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000371 AC: 45

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	Severe myoclonic epilepsy in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	0.033
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	0.51	N
PhyloP100		4.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.44	N
REVEL	Uncertain	0.44
Sift	Benign	0.23	T
Sift4G	Benign	0.47	T
Polyphen		0.085	B
Vest4		0.34
MVP		0.42
MPC		0.72
ClinPred		0.059	T
GERP RS		5.3
Varity_R		0.15
gMVP		0.87
Mutation Taster		=13/87	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: rs138231868; hg19: chr2-166854631;