rs121917931

Variant names:

• chr2-166073402-A-G
• rs121917931
• NM_001165963.4:c.220T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001165963.4(SCN1A):​c.220T>C​(p.Ser74Pro) 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.73
• Publications: 5 publications found

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

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001165963.4
• PM2: Very rare variant in population databases, with high coverage
• 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 familial or sporadic hemiplegic migraine, myoclonic-astatic epilepsy, arthrogryposis, Dravet syndrome, malignant migrating partial seizures of infancy, generalized epilepsy with febrile seizures plus, type 2, migraine, familial hemiplegic, 3, developmental and epileptic encephalopathy, 6A, familial hemiplegic migraine, generalized epilepsy with febrile seizures plus, genetic developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.220T>C	p.Ser74Pro	missense_variant	Exon 4 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.220T>C	p.Ser74Pro	missense_variant	Exon 4 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.220T>C	p.Ser74Pro	missense_variant	Exon 3 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.220T>C	p.Ser74Pro	missense_variant	Exon 1 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.220T>C	p.Ser74Pro	missense_variant	Exon 3 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 1 Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;.;.;M;M;.;M;M;M;M
PhyloP100		2.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0060	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.0090	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0	.;.;.;.;D;.;.;D;D;.
Vest4		0.69, 0.84, 0.78, 0.75
MutPred		0.47		Loss of phosphorylation at S74 (P = 0.0368);Loss of phosphorylation at S74 (P = 0.0368);Loss of phosphorylation at S74 (P = 0.0368);Loss of phosphorylation at S74 (P = 0.0368);Loss of phosphorylation at S74 (P = 0.0368);Loss of phosphorylation at S74 (P = 0.0368);Loss of phosphorylation at S74 (P = 0.0368);Loss of phosphorylation at S74 (P = 0.0368);Loss of phosphorylation at S74 (P = 0.0368);Loss of phosphorylation at S74 (P = 0.0368);
MVP		0.99
MPC		0.85
ClinPred		0.96	D
GERP RS		4.3
PromoterAI		-0.015	Neutral
Varity_R		0.57
gMVP		0.96
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs121917931; hg19: chr2-166929912;