rs2298771

Variant names:

• chr2-166036278-C-T
• rs2298771
• NM_001165963.4:c.3199G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-166036278-C-T
• chr2-166036278-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001165963.4(SCN1A):​c.3199G>A​(p.Ala1067Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,613,022 control chromosomes in the GnomAD database, including 404,559 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1067E) has been classified as Uncertain significance. The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.74 (41764 hom., cov: 32)
  • Exomes 𝑓: 0.70 (362795 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.310
• Publications: 106 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

Specifications for SCN1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the SCN1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 848 curated pathogenic missense variants (we use a threshold of 10). The gene has 89 curated benign missense variants. Gene score misZ: 5.2206 (above the threshold of 3.09). Trascript score misZ: 7.6022 (above the threshold of 3.09). GenCC associations: The gene is linked to generalized epilepsy with febrile seizures plus, type 2, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, Lennox-Gastaut syndrome, malignant migrating partial seizures of infancy, Dravet syndrome, myoclonic-astatic epilepsy, familial or sporadic hemiplegic migraine, migraine, familial hemiplegic, 3, genetic developmental and epileptic encephalopathy, arthrogryposis.
• BP4: Computational evidence support a benign effect (MetaRNN=7.491045E-7).
• BP6: Variant 2-166036278-C-T is Benign according to our data. Variant chr2-166036278-C-T is described in ClinVar as Benign. ClinVar VariationId is 36753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

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.3199G>A	p.Ala1067Thr	missense	Exon 19 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.3199G>A	p.Ala1067Thr	missense	Exon 18 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.3199G>A	p.Ala1067Thr	missense	Exon 17 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.3199G>A	p.Ala1067Thr	missense	Exon 19 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.3199G>A	p.Ala1067Thr	missense	Exon 18 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.3166G>A	p.Ala1056Thr	missense	Exon 16 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.737 AC: 112081 AN: 152006 Hom.: 41719 Cov.: 32

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.681

GnomAD2 exomes AF: 0.726 AC: 181805 AN: 250522 AF XY: 0.715

Gnomad AFR exome AF: 0.829

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.896

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.702 AC: 1026255 AN: 1460898 Hom.: 362795 Cov.: 47 AF XY: 0.699 AC XY: 507991 AN XY: 726822

African (AFR) AF: 0.827 AC: 27658 AN: 33456

American (AMR) AF: 0.803 AC: 35863 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15708 AN: 26120

East Asian (EAS) AF: 0.895 AC: 35496 AN: 39648

South Asian (SAS) AF: 0.683 AC: 58896 AN: 86212

European-Finnish (FIN) AF: 0.748 AC: 39945 AN: 53388

Middle Eastern (MID) AF: 0.512 AC: 2949 AN: 5762

European-Non Finnish (NFE) AF: 0.691 AC: 767751 AN: 1111278

Other (OTH) AF: 0.696 AC: 41989 AN: 60352

GnomAD4 genome AF: 0.737 AC: 112187 AN: 152124 Hom.: 41764 Cov.: 32 AF XY: 0.741 AC XY: 55088 AN XY: 74356

African (AFR) AF: 0.823 AC: 34151 AN: 41498

American (AMR) AF: 0.742 AC: 11343 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2091 AN: 3470

East Asian (EAS) AF: 0.891 AC: 4600 AN: 5164

South Asian (SAS) AF: 0.709 AC: 3422 AN: 4824

European-Finnish (FIN) AF: 0.756 AC: 8004 AN: 10590

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46395 AN: 67980

Other (OTH) AF: 0.684 AC: 1440 AN: 2106

Alfa AF: 0.704 Hom.: 73366

Bravo AF: 0.740

TwinsUK AF: 0.704 AC: 2611

ALSPAC AF: 0.690 AC: 2658

ESP6500AA AF: 0.816 AC: 3597

ESP6500EA AF: 0.675 AC: 5809

ExAC AF: 0.725 AC: 88032

Asia WGS AF: 0.790 AC: 2743 AN: 3474

EpiCase AF: 0.674

EpiControl AF: 0.655

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Epilepsy (1)
-	-	1	Generalized epilepsy with febrile seizures plus (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Migraine, familial hemiplegic, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	2.4
DANN	Benign	0.80
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.054	T
MetaRNN	Benign	7.5e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.49	N
PhyloP100		-0.31
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.27
Sift	Benign	0.64	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.70
ClinPred		0.0066	T
GERP RS		-2.9
Varity_R		0.11
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs2298771; hg19: chr2-166892788; COSMIC: COSV57690547; COSMIC: COSV57690547;