chr2-166002577-A-T

Variant names:

• chr2-166002577-A-T
• rs772400574
• NM_001165963.4:c.4179T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 7P and 2B. PM1 PM2 PM5 PP2 BP4_Moderate

The NM_001165963.4(SCN1A):​c.4179T>A​(p.His1393Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1393Y) has been classified as Uncertain significance. The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.211
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-166002578-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1705829.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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=0.112268895).

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.4179T>A	p.His1393Gln	missense	Exon 24 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.4179T>A	p.His1393Gln	missense	Exon 23 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.4179T>A	p.His1393Gln	missense	Exon 22 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.4179T>A	p.His1393Gln	missense	Exon 24 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.4179T>A	p.His1393Gln	missense	Exon 23 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.4146T>A	p.His1382Gln	missense	Exon 21 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151746 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460136 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726386

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110926

Other (OTH) AF: 0.0000332 AC: 2 AN: 60270

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151746 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74094

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15186

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67804

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

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.84
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	-0.38	N
PhyloP100		0.21
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.30
Sift	Benign	0.18	T
Sift4G	Uncertain	0.018	D
Polyphen		0.0	B
Vest4		0.38
MutPred		0.53		Loss of catalytic residue at H1393 (P = 0.012)
MVP		0.49
MPC		0.78
ClinPred		0.091	T
GERP RS		3.0
Varity_R		0.052
gMVP		0.91
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs772400574; hg19: chr2-166859087;