2-165998133-G-T

Variant names:

• chr2-165998133-G-T
• rs121918772
• NM_001165963.4:c.4381C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001165963.4(SCN1A):​c.4381C>A​(p.Leu1461Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,454,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.476

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)

LOC102724058 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3494049).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4381C>A	p.Leu1461Ile	missense_variant	Exon 26 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4381C>A	p.Leu1461Ile	missense_variant	Exon 26 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4381C>A	p.Leu1461Ile	missense_variant	Exon 25 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4348C>A	p.Leu1450Ile	missense_variant	Exon 23 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4297C>A	p.Leu1433Ile	missense_variant	Exon 23 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249322 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1454774 Hom.: 0 Cov.: 29 AF XY: 0.00000553 AC XY: 4 AN XY: 723878

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Severe myoclonic epilepsy in infancy Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;.;.;D;.;.;D;.;.;.
Eigen	Benign	0.048
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.46	T;T;T;T;.;T;.;.;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.51	.;.;.;N;.;.;N;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.72	.;.;.;N;.;.;N;.;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.59	.;.;.;T;.;.;T;.;T;T
Sift4G	Benign	0.35	.;.;.;T;.;.;T;.;T;T
Polyphen		0.88, 0.98	.;.;.;P;D;.;P;D;D;.
Vest4		0.32, 0.37, 0.39, 0.37
MutPred		0.50		.;.;.;Gain of sheet (P = 0.0149);.;.;Gain of sheet (P = 0.0149);.;.;.;
MVP		0.97
MPC		0.89
ClinPred		0.43	T
GERP RS		4.4
Varity_R		0.070
gMVP		0.83

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: rs121918772; hg19: chr2-166854643;