rs373967247
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP2BP4_StrongBP6_Very_StrongBS2
The NM_001165963.4(SCN1A):āc.4855A>Gā(p.Met1619Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000259 in 1,613,334 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Consequence
NM_001165963.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.4855A>G | p.Met1619Val | missense_variant, splice_region_variant | 29/29 | ENST00000674923.1 | |
LOC102724058 | NR_110598.1 | n.176-23193T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.4855A>G | p.Met1619Val | missense_variant, splice_region_variant | 29/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.193-23193T>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 151868Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000514 AC: 129AN: 250748Hom.: 3 AF XY: 0.000679 AC XY: 92AN XY: 135530
GnomAD4 exome AF: 0.000274 AC: 401AN: 1461354Hom.: 7 Cov.: 31 AF XY: 0.000415 AC XY: 302AN XY: 726998
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 151980Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74258
ClinVar
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2018 | Reported in the heterozygous state in an individual with intractable epilepsy (Wang et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23195492) - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | SCN1A: PP2, BS1, BS2 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 29, 2018 | Variant summary: SCN1A c.4855A>G (p.Met1619Val) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 245532 control chromosomes, predominantly within the South Asian subpopulation in the gnomAD database at a frequency of 0.004, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 320-fold above the estimated maximal expected allele frequency for a pathogenic variant in SCN1A causing Intractable Childhood Epilepsy with Generalized Tonic-Clonic seizures phenotype (1.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.4855A>G, has been reported in the literature in one individual affected with Intractable Childhood Epilepsy (Wang_2012). This report does not provide unequivocal conclusions about association of the variant with Intractable Childhood Epilepsy with Generalized Tonic-Clonic seizures. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | - - |
SCN1A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 05, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Severe myoclonic epilepsy in infancy Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at