rs121918757

Variant names:

• chr2-165991853-A-G
• rs121918757
• NM_001165963.4:c.5422T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001165963.4(SCN1A):​c.5422T>C​(p.Phe1808Leu) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1808I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.26
• Publications: 9 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: Pathogenic. The variant received 15 ACMG points.

• PS1: Transcript NM_001165963.4 (SCN1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 3897808
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr2-165991853-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 4073664.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, 0.93
• PP5: Variant 2-165991853-A-G is Pathogenic according to our data. Variant chr2-165991853-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 68661.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.5422T>C	p.Phe1808Leu	missense_variant	Exon 29 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.5422T>C	p.Phe1808Leu	missense_variant	Exon 29 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.5422T>C	p.Phe1808Leu	missense_variant	Exon 28 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.5389T>C	p.Phe1797Leu	missense_variant	Exon 26 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.5338T>C	p.Phe1780Leu	missense_variant	Exon 28 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in an individual with intractable childhood epilepsy with generalized tonic-clonic seizures (Fujiwara T et al., 2003) and in an individual with Dravet syndrome (Berkvens JJ et al., 2015); Published functional studies demonstrate that the variant disrupts normal sodium channel function (Rhoades TH et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 15346159, 15277629, 23884151, 26005841, 26076853, 28102150, 31086826, 16210358, 12566275) -

Severe myoclonic epilepsy in infancy Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;D;.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;.;.;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;.;.;H;.;H;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	.;.;.;D;.;D;.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;.;D;.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;.;.;D;.;D;.;D;D
Polyphen		1.0	.;.;.;.;D;.;D;D;.
Vest4		0.75, 0.96, 0.95, 0.92
MutPred		0.67		.;.;.;Gain of disorder (P = 0.1804);.;Gain of disorder (P = 0.1804);.;.;.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.99
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: rs121918757; hg19: chr2-166848363;