chr2-166039436-C-T

Variant names:

• chr2-166039436-C-T
• rs398123588
• NM_001165963.4:c.2576G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.2576G>A​(p.Arg859His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000322016: Published functional studies suggest that p.R859H results in channel gating defects (Volkers et al., 2011" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R859C) has been classified as Pathogenic. The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.90
• Publications: 20 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)

ACMG classification

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

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322016: Published functional studies suggest that p.R859H results in channel gating defects (Volkers et al., 2011; Volkers et al., 2013); SCV000633829: Experimental studies have shown that this missense change affects SCN1A function (PMID: 21864321, 24277604).; SCV000920184: The most pronounced variant effect leads to mixed functional defects in Nav1.1 gating although the mutant protein is produced at normal levels (Volkers_2011; Volkers_2013).; SCV004102878: "In vitro functional studies have shown that this variant negatively impacts sodium channel function (Volkers et al. 2011. PubMed ID: 21864321; Volkers et al. 2013. PubMed ID: 24277604)."
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr2-166039437-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 68592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 2-166039436-C-T is Pathogenic according to our data. Variant chr2-166039436-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 93639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2576G>A	p.Arg859His	missense	Exon 17 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.2576G>A	p.Arg859His	missense	Exon 16 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.2576G>A	p.Arg859His	missense	Exon 15 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.2576G>A	p.Arg859His	missense	Exon 17 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.2576G>A	p.Arg859His	missense	Exon 16 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.2543G>A	p.Arg848His	missense	Exon 14 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250370 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453400 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 723412

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5420

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105454

Other (OTH) AF: 0.00 AC: 0 AN: 60014

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Generalized epilepsy with febrile seizures plus, type 2 (2)
2	-	-	not provided (2)
1	-	-	Autosomal dominant epilepsy (1)
1	-	-	Developmental and epileptic encephalopathy (1)
1	-	-	SCN1A-related disorder (1)
-	1	-	Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.86		Loss of MoRF binding (P = 0.0338)
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs398123588; hg19: chr2-166895946;