rs121917983

Variant names:

• chr2-166054644-G-A
• rs121917983
• NM_001165963.4:c.596C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166054644-G-A
• chr2-166054644-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_001165963.4(SCN1A):​c.596C>T​(p.Thr199Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T199R) has been classified as Uncertain significance.

• 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: 3.81
• Publications: 5 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001165963.4
• 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 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.
• PP5: Variant 2-166054644-G-A is Pathogenic according to our data. Variant chr2-166054644-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430305.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.596C>T	p.Thr199Ile	missense_variant	Exon 7 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.596C>T	p.Thr199Ile	missense_variant	Exon 7 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.596C>T	p.Thr199Ile	missense_variant	Exon 6 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.596C>T	p.Thr199Ile	missense_variant	Exon 4 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.596C>T	p.Thr199Ile	missense_variant	Exon 6 of 28	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

not provided Pathogenic:1

Jul 28, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This substitution is predicted to be within the transmembrane segment S3 of the first homologous domain; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614) -

Developmental and epileptic encephalopathy Uncertain:1

Jun 29, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine with isoleucine at codon 199 of the SCN1A protein (p.Thr199Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with epilepsy (Invitae). ClinVar contains an entry for this variant (Variation ID: 430305). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;.;.;D;.;.;D;.;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T;T;T;.;T;.;.;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	-0.51	.;.;.;N;N;.;N;N;N;N
PhyloP100		3.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.14	.;.;.;N;.;.;N;.;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.17	.;.;.;T;.;.;T;.;T;T
Sift4G	Benign	0.47	.;.;.;T;.;.;T;.;T;T
Polyphen		1.0, 0.41	.;.;.;D;B;.;D;B;B;.
Vest4		0.76, 0.77, 0.76, 0.78
MutPred		0.50		Loss of catalytic residue at T199 (P = 0.0864);Loss of catalytic residue at T199 (P = 0.0864);Loss of catalytic residue at T199 (P = 0.0864);Loss of catalytic residue at T199 (P = 0.0864);Loss of catalytic residue at T199 (P = 0.0864);Loss of catalytic residue at T199 (P = 0.0864);Loss of catalytic residue at T199 (P = 0.0864);Loss of catalytic residue at T199 (P = 0.0864);Loss of catalytic residue at T199 (P = 0.0864);Loss of catalytic residue at T199 (P = 0.0864);
MVP		0.90
MPC		1.0
ClinPred		0.92	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.94
Mutation Taster		=4/96	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: rs121917983; hg19: chr2-166911154;