rs121918799

Variant names:

• chr2-166015636-G-C
• rs121918799
• NM_001165963.4:c.3521C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_001165963.4(SCN1A):​c.3521C>G​(p.Thr1174Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,612,736 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (11 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:13 O:1
• Conservation: PhyloP100: 3.46
• Publications: 36 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 -10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_001165963.4
• 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 familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010132015).
• BP6: Variant 2-166015636-G-C is Benign according to our data. Variant chr2-166015636-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68616.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00147 (224/151970) while in subpopulation NFE AF = 0.00234 (159/67844). AF 95% confidence interval is 0.00205. There are 0 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 224 AD,Unknown gene.

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.3521C>G	p.Thr1174Ser	missense	Exon 20 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.3521C>G	p.Thr1174Ser	missense	Exon 19 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.3521C>G	p.Thr1174Ser	missense	Exon 18 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.3521C>G	p.Thr1174Ser	missense	Exon 20 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.3521C>G	p.Thr1174Ser	missense	Exon 19 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.3488C>G	p.Thr1163Ser	missense	Exon 17 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 224 AN: 151852 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00165 AC: 415 AN: 251166 AF XY: 0.00177

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00165 AC: 2409 AN: 1460766 Hom.: 11 Cov.: 31 AF XY: 0.00169 AC XY: 1226 AN XY: 726646

African (AFR) AF: 0.000329 AC: 11 AN: 33452

American (AMR) AF: 0.000157 AC: 7 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000729 AC: 19 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86242

European-Finnish (FIN) AF: 0.00344 AC: 184 AN: 53414

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00188 AC: 2085 AN: 1111100

Other (OTH) AF: 0.00136 AC: 82 AN: 60334

GnomAD4 genome AF: 0.00147 AC: 224 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74284

African (AFR) AF: 0.000313 AC: 13 AN: 41526

American (AMR) AF: 0.0000656 AC: 1 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00234 AC: 159 AN: 67844

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.00215 Hom.: 1

Bravo AF: 0.00114

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00177 AC: 215

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	3	not specified (3)
-	-	2	Generalized epilepsy with febrile seizures plus, type 2 (2)
-	1	1	Migraine, familial hemiplegic, 3 (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Epilepsy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SCN1A-related disorder (1)
-	1	-	Seizure;C0494475:Bilateral tonic-clonic seizure;C4316903:Generalized non-motor (absence) seizure (1)
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)
-	-	1	Severe myoclonic epilepsy in infancy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.79
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.5	N
PhyloP100		3.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.21	N
REVEL	Uncertain	0.40
Sift	Benign	0.76	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.48
MutPred		0.29		Loss of glycosylation at T1174 (P = 0.0878)
MVP		0.85
MPC		0.64
ClinPred		0.021	T
GERP RS		5.4
Varity_R		0.13
gMVP		0.50
Mutation Taster		=100/0	polymorphism

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: rs121918799; hg19: chr2-166872146;