NM_001165963.4:c.235G>A

Variant names:

• chr2-166073387-C-T
• rs121917982
• NM_001165963.4:c.235G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001165963.4(SCN1A):​c.235G>A​(p.Asp79Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D79H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.89
• Publications: 10 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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr2-166073386-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3634069.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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 2-166073387-C-T is Pathogenic according to our data. Variant chr2-166073387-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 379355.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.235G>A	p.Asp79Asn	missense_variant	Exon 4 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.235G>A	p.Asp79Asn	missense_variant	Exon 4 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.235G>A	p.Asp79Asn	missense_variant	Exon 3 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.235G>A	p.Asp79Asn	missense_variant	Exon 1 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.235G>A	p.Asp79Asn	missense_variant	Exon 3 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 22, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The D79N missense variant in the SCN1A gene has been reported previously as de novo in an individual with Dravet syndrome (Zuberi et al., 2011). In addition, a different amino acid substitution at this position (D79H) has been reported de novo in an individual with severe myoclonic epilepsy of infancy (Harkin et al., 2007; SCN1A Variant Database). D79N is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution alters a conserved position predicted to be in the N-terminal region of the SCN1A protein, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (S74P, E78D, Y84C) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We therefore interpret D79N as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;.;.;H;H;.;H;H;H;H
PhyloP100		7.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.6	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0	.;.;.;.;D;.;.;D;D;.
Vest4		0.77, 0.81, 0.82, 0.78
MutPred		0.62		Loss of phosphorylation at S74 (P = 0.108);Loss of phosphorylation at S74 (P = 0.108);Loss of phosphorylation at S74 (P = 0.108);Loss of phosphorylation at S74 (P = 0.108);Loss of phosphorylation at S74 (P = 0.108);Loss of phosphorylation at S74 (P = 0.108);Loss of phosphorylation at S74 (P = 0.108);Loss of phosphorylation at S74 (P = 0.108);Loss of phosphorylation at S74 (P = 0.108);Loss of phosphorylation at S74 (P = 0.108);
MVP		0.99
MPC		0.98
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.0092	Neutral
Varity_R		0.80
gMVP		0.93
Mutation Taster		=0/100	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: rs121917982; hg19: chr2-166929897;