2-165354227-C-T
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_001040142.2(SCN2A):c.2955C>T(p.Ser985=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,614,022 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 23 hom. )
Consequence
SCN2A
NM_001040142.2 synonymous
NM_001040142.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.87
Genes affected
SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
Variant 2-165354227-C-T is Benign according to our data. Variant chr2-165354227-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139009.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4, Likely_benign=1}.
BP7
Synonymous conserved (PhyloP=-2.87 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00235 (358/152234) while in subpopulation NFE AF= 0.00149 (101/68004). AF 95% confidence interval is 0.00125. There are 1 homozygotes in gnomad4. There are 247 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 358 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.2955C>T | p.Ser985= | synonymous_variant | 17/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.2955C>T | p.Ser985= | synonymous_variant | 17/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.2955C>T | p.Ser985= | synonymous_variant | 17/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.2955C>T | p.Ser985= | synonymous_variant | 17/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes AF: 0.00235 AC: 358AN: 152116Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00306 AC: 770AN: 251370Hom.: 8 AF XY: 0.00294 AC XY: 399AN XY: 135874
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GnomAD4 exome AF: 0.00139 AC: 2034AN: 1461788Hom.: 23 Cov.: 32 AF XY: 0.00137 AC XY: 998AN XY: 727202
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GnomAD4 genome AF: 0.00235 AC: 358AN: 152234Hom.: 1 Cov.: 32 AF XY: 0.00332 AC XY: 247AN XY: 74436
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 19, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2017 | This alteration is classified as 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. - |
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | SCN2A: BP4, BP7, BS1 - |
Seizures, benign familial infantile, 3 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at