NM_001165963.4:c.4465C>A

Variant names:

• chr2-165998049-G-T
• rs121918628
• NM_001165963.4:c.4465C>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PM1 PS3 PP1_Strong PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.4465C>A variant in SCN1A is a missense variant predicted to cause substitution of glutamine by lysine at amino acid 1489 (p.Gln1489Lys). This variant has been reported to segregate with hemiplegic migraine in 18 affected individuals from 3 families (PMID:16054936) (PP1_strong). This variant is absent from gnomAD (v4) (PM2_supporting). Whole-cell voltage-clamp studies were performed on human tsA201 cell model that showed increased persistent current but also enhanced entry into slow activation as well as delayed recovery from fast and slow inactivation indicating that this variant impacts protein function (PMIDs: 18621678, 18632931) (PS3). This variant resides within a Pathogenic Enriched Region that is defined as a mutational hotspot by the ClinGen Epilepsy Sodium Channel VCEP (PM1). The computational predictor (REVEL) gives a score of 0.936, evidence that correlates with impact to SCN1A function (PP3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hemiplegic migraine based on ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PP1_strong, PS3, PP3_moderate, PM1, PM2_supporting (v1.0; approved September 24, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA256608/MONDO:0000700/067

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:2
• Conservation: PhyloP100: 9.91

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 Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4465C>A	p.Gln1489Lys	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.4465C>A	p.Gln1489Lys	missense_variant	Exon 26 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4465C>A	p.Gln1489Lys	missense_variant	Exon 25 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4432C>A	p.Gln1478Lys	missense_variant	Exon 23 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.1	c.4381C>A	p.Gln1461Lys	missense_variant	Exon 23 of 26	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451728 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 722606

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Migraine, familial hemiplegic, 3 Pathogenic:1 Other:1

Jul 30, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Severe myoclonic epilepsy in infancy Other:1

-

Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	.;.;.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;D;.;.;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;.;.;H;.;.;H;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.6	.;.;.;D;.;.;D;.;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;.;D;.;.;D;.;D;D
Sift4G	Uncertain	0.030	.;.;.;D;.;.;D;.;D;D
Polyphen		1.0, 0.99	.;.;.;D;D;.;D;D;D;.
Vest4		0.76, 0.92, 0.90, 0.81
MutPred		0.55		.;.;.;Gain of methylation at Q1489 (P = 0.0072);.;.;Gain of methylation at Q1489 (P = 0.0072);.;.;.;
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918628; hg19: chr2-166854559;