rs780607306

Variant names:

• chr2-166013893-C-A
• rs780607306
• NM_001165963.4:c.3556G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166013893-C-A
• chr2-166013893-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP6 BS2

The NM_001165963.4(SCN1A):​c.3556G>T​(p.Val1186Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,611,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1186I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.33
• Publications: 0 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_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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.
• BP6: Variant 2-166013893-C-A is Benign according to our data. Variant chr2-166013893-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206804.
• BS2: High AC in GnomAdExome4 at 14 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.3556G>T	p.Val1186Leu	missense	Exon 21 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.3556G>T	p.Val1186Leu	missense	Exon 20 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.3556G>T	p.Val1186Leu	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.3556G>T	p.Val1186Leu	missense	Exon 21 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.3556G>T	p.Val1186Leu	missense	Exon 20 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.3523G>T	p.Val1175Leu	missense	Exon 18 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151690 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250334 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459490 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726060

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.000201 AC: 9 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110610

Other (OTH) AF: 0.0000663 AC: 4 AN: 60306

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151690 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74082

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.000132 AC: 2 AN: 15170

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67726

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.36	T
Polyphen		0.0050	B
Vest4		0.65
MutPred		0.67		Gain of catalytic residue at V1186 (P = 0.0205)
MVP		0.83
MPC		1.4
ClinPred		0.24	T
GERP RS		5.8
Varity_R		0.60
gMVP		0.89
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780607306; hg19: chr2-166870403;