rs144691638
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 5P and 7B. PM1PM5PP2BP4_ModerateBP6BS2
The NM_001165963.4(SCN1A):c.5568G>A(p.Met1856Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000725 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. M1856T) 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_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.5568G>A | p.Met1856Ile | missense_variant | 29/29 | ENST00000674923.1 | |
LOC102724058 | NR_110598.1 | n.176-23906C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.5568G>A | p.Met1856Ile | missense_variant | 29/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.193-23906C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000349 AC: 53AN: 152006Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000108 AC: 27AN: 250732Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135470
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461752Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37AN XY: 727192
GnomAD4 genome ? AF: 0.000348 AC: 53AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 28, 2016 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 14, 2022 | Variant summary: SCN1A c.5568G>A (p.Met1856Ile) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 250732 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 78 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN1A causing SCN1A-Related Seizure Disorder phenotype (1.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.5568G>A in individuals affected with SCN1A-Related Seizure Disorder and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classifed the variant as VUS (n=1) and benign/likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 10, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at