rs1295072436
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2
The NM_001165963.4(SCN1A):āc.4171A>Cā(p.Asn1391His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1391S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001165963.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.4171A>C | p.Asn1391His | missense_variant | 24/29 | ENST00000674923.1 | NP_001159435.1 | |
LOC102724058 | NR_110598.1 | n.176-13028T>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.4171A>C | p.Asn1391His | missense_variant | 24/29 | NM_001165963.4 | ENSP00000501589 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.193-13028T>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151762Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250566Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135420
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460180Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726398
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151762Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74114
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2016 | The p.N1391H variant (also known as c.4171A>C), located in coding exon 21 of the SCN1A gene, results from an A to C substitution at nucleotide position 4171. The asparagine at codon 1391 is replaced by histidine, an amino acid with similar properties. A different alteration at the same position, p.N1391S, has been identified in a patient with classic Dravet syndrome (Depienne C et al, J. Med. Genet. 2009 Mar; 46(3):183-91). The p.N1391H variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 17, 2023 | The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This substitution is predicted to be within the extracellular loop between the S5 and S6 transmembrane segments of the third homologous domain; This variant is associated with the following publications: (PMID: 32347949, 18930999) - |
SCN1A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has not been previously reported or functionally characterized in the literature to our knowledge. A different missense change at the same codon (c.4172A>G, p.Asn1391Ser) has been previously reported as a heterozygous change in a patient with Dravet syndrome (PMID: 18930999). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/250566) and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.4171A>C (p.Asn1391His) variant is classified as Variant of Uncertain Significance. - |
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 10, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at