2-166037860-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_001165963.4(SCN1A):c.2862G>C(p.Glu954Asp) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E954G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.84

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-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript NM_001165963.4 (SCN1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 530535
• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr2-166037861-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2020613.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, SCN1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant 2-166037860-C-G is Pathogenic according to our data. Variant chr2-166037860-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1071810.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.2862G>C	p.Glu954Asp	missense_variant	18/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.2862G>C	p.Glu954Asp	missense_variant	18/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+1730C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 19, 2020

This sequence change replaces glutamic acid with aspartic acid at codon 954 of the SCN1A protein (p.Glu954Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN1A-related conditions. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different variant (c.2862G>T) giving rise to the same protein effect observed here (p.Glu954Asp) has been determined to be pathogenic (Invitae). This suggests that this variant is also likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
Polyphen		0.99, 0.18	.;.;.;D;B;.;D;B;B;.
Vest4		0.73, 0.80, 0.81, 0.82
MutPred		0.56		.;Loss of helix (P = 0.0041);.;Loss of helix (P = 0.0041);.;.;Loss of helix (P = 0.0041);.;.;.;
MVP		0.85
MPC		2.5
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.82
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-166894370;