rs1553549660

Positions:

• chr2-166051842-G-A
• chr2-166051842-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3 PP5

The NM_001165963.4(SCN1A):​c.841C>T​(p.Pro281Ser) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P281A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.84

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN1A. . Gene score misZ 5.2206 (greater than the threshold 3.09). Trascript score misZ 7.6022 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.802
• PP5: Variant 2-166051842-G-A is Pathogenic according to our data. Variant chr2-166051842-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 976292.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.841C>T	p.Pro281Ser	missense_variant	9/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.841C>T	p.Pro281Ser	missense_variant	9/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.841C>T	p.Pro281Ser	missense_variant	8/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.841C>T	p.Pro281Ser	missense_variant	6/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.841C>T	p.Pro281Ser	missense_variant	6/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Apr 05, 2024

Criteria applied: PM5_STR,PS4_MOD,PM2,PP2,PP3,PS2_MOD -

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Pro281 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18930999, 27734276). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 976292). This missense change has been observed in individual(s) with SCN1A-related conditions (PMID: 18930999). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 281 of the SCN1A protein (p.Pro281Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;.;.;D;.;.;D;.;.;.
Eigen	Benign	0.062
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D;D;.;D;.;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.4	.;.;.;L;L;.;L;L;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.1	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	.;.;.;D;.;.;D;.;D;D
Sift4G	Benign	0.26	.;.;.;T;.;.;T;.;T;T
Polyphen		0.017, 0.012	.;.;.;B;B;.;B;B;B;.
Vest4		0.76, 0.83, 0.79, 0.73
MutPred		0.66		Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);Gain of disorder (P = 0.1024);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.56
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553549660; hg19: chr2-166908352;