rs1553545770

chr2-166045270-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_001165963.4(SCN1A):c.1435C>A(p.Leu479Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L479P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.11

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.25319636).
• BP6: Variant 2-166045270-G-T is Benign according to our data. Variant chr2-166045270-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 530506.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.1435C>A	p.Leu479Ile	missense_variant	13/29	ENST00000674923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.1435C>A	p.Leu479Ile	missense_variant	13/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.487+9140G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T;T;T;T;.;T;.;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.72	D;D;D;D
PrimateAI	Uncertain	0.55	T
Polyphen		0.82, 0.89	.;.;.;P;P;.;P;P;P;.
Vest4		0.32, 0.30, 0.31, 0.28
MutPred		0.36		.;Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);
MVP		0.58
MPC		0.76
ClinPred		0.43	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.49

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: rs1553545770; hg19: chr2-166901780;