2-166036311-T-G

Position:

• chr2-166036311-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001165963.4(SCN1A):​c.3166A>C​(p.Asn1056His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.3166A>C	p.Asn1056His	missense_variant	19/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.3166A>C	p.Asn1056His	missense_variant	19/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.3166A>C	p.Asn1056His	missense_variant	18/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.3133A>C	p.Asn1045His	missense_variant	16/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.3082A>C	p.Asn1028His	missense_variant	16/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461322 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726932

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2020

Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be in the cytoplasmic loop between the second and third homologous domains; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;.;.;D;.;.;D;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;T;T;.;T;.;.;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.8	.;.;.;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.5	.;.;.;D;.;.;D;.;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	.;.;.;D;.;.;D;.;D;D
Sift4G	Benign	0.16	.;.;.;T;.;.;T;.;T;T
Polyphen		0.32, 0.96	.;.;.;B;D;.;B;D;D;.
Vest4		0.39, 0.34, 0.34, 0.31
MutPred		0.40		.;Loss of stability (P = 0.0648);.;Loss of stability (P = 0.0648);.;.;Loss of stability (P = 0.0648);.;.;.;
MVP		0.96
MPC		0.77
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.29
gMVP		0.31

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: chr2-166892821;