rs121917907

Positions:

• chr2-166073435-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001165963.4(SCN1A):​c.187T>C​(p.Phe63Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.43

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 127) in uniprot entity SCN1A_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_001165963.4
• 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.187T>C	p.Phe63Leu	missense_variant	4/29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.187T>C	p.Phe63Leu	missense_variant	4/29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.187T>C	p.Phe63Leu	missense_variant	3/28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.187T>C	p.Phe63Leu	missense_variant	1/26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.187T>C	p.Phe63Leu	missense_variant	1/26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Severe myoclonic epilepsy in infancy Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.81	.;.;.;D;.;.;D;.;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.62	T;T;T;T;.;T;.;.;T;T
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.9	.;.;.;L;L;.;L;L;L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.1	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.10	.;.;.;T;.;.;T;.;T;T
Sift4G	Benign	0.63	.;.;.;T;.;.;T;.;T;T
Polyphen		0.10	.;.;.;.;B;.;.;B;B;.
Vest4		0.48, 0.76, 0.71, 0.61
MutPred		0.58		Gain of disorder (P = 0.1519);Gain of disorder (P = 0.1519);Gain of disorder (P = 0.1519);Gain of disorder (P = 0.1519);Gain of disorder (P = 0.1519);Gain of disorder (P = 0.1519);Gain of disorder (P = 0.1519);Gain of disorder (P = 0.1519);Gain of disorder (P = 0.1519);Gain of disorder (P = 0.1519);
MVP		0.99
MPC		1.0
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.42
gMVP		0.86

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: rs121917907; hg19: chr2-166929945;