rs780809852

chr2-165991774-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP2

The NM_001165963.4(SCN1A):c.5501C>T(p.Ala1834Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1834A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SCN1A NM_001165963.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6
• Conservation: PhyloP100: 8.06

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001165963.4
• PP2: Missense variant where missense usually causes diseases, SCN1A

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN1A	NM_001165963.4	c.5501C>T	p.Ala1834Val	missense_variant	29/29	ENST00000674923.1
LOC102724058	NR_110598.1	n.176-23839G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN1A	ENST00000674923.1	c.5501C>T	p.Ala1834Val	missense_variant	29/29		NM_001165963.4	P4
SCN1A-AS1	ENST00000651574.1	n.193-23839G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250870 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135570

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727190

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000936 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	SCN1A: PP2, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2017	p.Ala1834Val (GCG>GTG): c.5501 C>T in exon 26 of the SCN1A gene (NM_001165963.1) The Ala1834Val missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one uncharged, non-polar amino acid for another at a position that is conserved in placental mammals but is not conserved in more distantly related species. However, it alters a position between the sixth transmembrane domain and the IQ domain and other missense mutations associated with Dravet syndrome (Phe1831Ser, Ala1832Pro, Leu1835Phe) have been reported in this region of the protein. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ala1834Val is a disease-causing mutation or a rare benign variant.The variant is found in INFANT-EPI panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 19, 2023	- -

Severe myoclonic epilepsy in infancy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -

Severe myoclonic epilepsy in infancy;C1858673:Generalized epilepsy with febrile seizures plus, type 2;C5543353:Developmental and epileptic encephalopathy 6B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Lifecell International Pvt. Ltd

-

The missense variant NM_001165963.4 (SCN1A):c.5501C>T (p.Ala1834Val) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala1834Val variant is observed in 2/30,616 (0.0065%) alleles from individuals of gnomAD South Asian background in gnomAD. The p.Ala1834Val variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between alanine and valine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene SCN1A has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 5.22. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). The Missense Badness and MPC scores for this variant is 0.35 and 1.56 respectively. Missense Badness Score is the normalized fold difference of missense substitutions between observed and expected variants from ExAC dataset. This score is then combined with orthogonal deleteriousness metrics into one score called MPC (for Missense badness, PolyPhen-2, and Constraint) designed to classify whether a missense variants is deleterious.Variants with MPC ≥ 2 have a rate nearly 6 times higher in cases than in controls. While those with intermediate MPC values (1 ≤ MPC < 2) have a more modest excess in cases. The gene SCN1A contains 537 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 4 variants within 6 amino acid positions of the variant p.Ala1834Val have been shown to be pathogenic, while none have been shown to be benign. The p.Ala1834Val missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 1834 of SCN1A is conserved in all mammalian species. The nucleotide c.5501 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Generalized epilepsy with febrile seizures plus, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D;D;.;.;.;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
Polyphen		0.89	.;.;.;.;P;.;P;P;.
Vest4		0.40, 0.48, 0.47, 0.63
MutPred		0.41		.;.;.;Loss of disorder (P = 0.0662);.;Loss of disorder (P = 0.0662);.;.;.;
MVP		0.91
MPC		1.6
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.55
gMVP		0.89

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: rs780809852; hg19: chr2-166848284; COSMIC: COSV100319388; COSMIC: COSV100319388;