2-166056450-A-G

Variant names:

• chr2-166056450-A-G
• rs121918631
• NM_001165963.4:c.434T>C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001165963.4(SCN1A):​c.434T>C​(p.Met145Thr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar 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, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 9.23

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

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 migraine, familial hemiplegic, 3, familial hemiplegic migraine, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, myoclonic-astatic epilepsy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 6, familial or sporadic hemiplegic migraine, arthrogryposis, Lennox-Gastaut syndrome, generalized epilepsy with febrile seizures plus, type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 2-166056450-A-G is Pathogenic according to our data. Variant chr2-166056450-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.434T>C	p.Met145Thr	missense_variant	Exon 6 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.434T>C	p.Met145Thr	missense_variant	Exon 6 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.434T>C	p.Met145Thr	missense_variant	Exon 5 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.434T>C	p.Met145Thr	missense_variant	Exon 3 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.434T>C	p.Met145Thr	missense_variant	Exon 3 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456296 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C1864987:Migraine, familial hemiplegic, 3;C5543353:Developmental and epileptic encephalopathy 6B Pathogenic:1

Feb 02, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PM1,PM2_P,PM5,PS3,PP3,PP5 ; Variant was found in heterozygous state -

not provided Pathogenic:1

Jun 08, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The M145T missense variant in the SCN1A gene has been reported previously to co-segregate with febrile seizures in a large family, and functional studies demonstrated abnormalities consistent with a loss-of-function pathogenic variant (Mantegazza et al., 2005; Colosimo et al., 2007). The M145T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M145T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution alters a highly conserved position predicted to be within the transmembrane segment S1 of the first homologous domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant at the same position (M145V) has been reported in the Human Gene Mutation Database in association with Dravet syndrome (Stenson et al., 2014). -

Febrile seizures, familial, 3a Pathogenic:1

Dec 13, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Generalized epilepsy with febrile seizures plus, type 2 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Severe myoclonic epilepsy in infancy Other:1

-

Channelopathy-Associated Epilepsy Research Center

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	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;.;.;H;H;.;H;H;H;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.5	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Polyphen		0.97, 1.0	.;.;.;D;D;.;D;D;D;.
Vest4		0.91, 0.97, 0.90, 0.96
MutPred		0.65		Loss of catalytic residue at M147 (P = 0.0269);Loss of catalytic residue at M147 (P = 0.0269);Loss of catalytic residue at M147 (P = 0.0269);Loss of catalytic residue at M147 (P = 0.0269);Loss of catalytic residue at M147 (P = 0.0269);Loss of catalytic residue at M147 (P = 0.0269);Loss of catalytic residue at M147 (P = 0.0269);Loss of catalytic residue at M147 (P = 0.0269);Loss of catalytic residue at M147 (P = 0.0269);Loss of catalytic residue at M147 (P = 0.0269);
MVP		0.98
MPC		0.78
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918631; hg19: chr2-166912960;