rs138123155
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_001040142.2(SCN2A):c.5326C>T(p.Leu1776=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000941 in 1,614,030 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0051 ( 8 hom., cov: 32)
Exomes 𝑓: 0.00051 ( 7 hom. )
Consequence
SCN2A
NM_001040142.2 synonymous
NM_001040142.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.16
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 -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
?
Variant 2-165389132-C-T is Benign according to our data. Variant chr2-165389132-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165389132-C-T is described in Lovd as [Benign]. Variant chr2-165389132-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=1.16 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00509 (774/152194) while in subpopulation AFR AF= 0.0178 (741/41542). AF 95% confidence interval is 0.0168. There are 8 homozygotes in gnomad4. There are 399 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 774 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.5326C>T | p.Leu1776= | synonymous_variant | 27/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.5326C>T | p.Leu1776= | synonymous_variant | 27/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.5326C>T | p.Leu1776= | synonymous_variant | 27/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.5326C>T | p.Leu1776= | synonymous_variant | 27/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? AF: 0.00508 AC: 772AN: 152076Hom.: 8 Cov.: 32
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GnomAD3 exomes AF: 0.00135 AC: 339AN: 251010Hom.: 2 AF XY: 0.00106 AC XY: 144AN XY: 135652
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GnomAD4 exome AF: 0.000510 AC: 745AN: 1461836Hom.: 7 Cov.: 33 AF XY: 0.000452 AC XY: 329AN XY: 727216
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GnomAD4 genome ? AF: 0.00509 AC: 774AN: 152194Hom.: 8 Cov.: 32 AF XY: 0.00536 AC XY: 399AN XY: 74398
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 2014 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 06, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 28, 2020 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2016 | 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;C5394520:Episodic ataxia, type 9 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 14, 2022 | - - |
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
SCN2A-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 29, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
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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Name
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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