rs771845478
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2
The ENST00000359125.7(KCNQ2):c.1347C>T(p.Gly449=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000735 in 1,605,116 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).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000076 ( 0 hom. )
Consequence
KCNQ2
ENST00000359125.7 synonymous
ENST00000359125.7 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.698
Genes affected
KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP7
Synonymous conserved (PhyloP=-0.698 with no splicing effect.
BS2
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.1347C>T | p.Gly449= | synonymous_variant | 13/17 | ENST00000359125.7 | NP_742105.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.1347C>T | p.Gly449= | synonymous_variant | 13/17 | 1 | NM_172107.4 | ENSP00000352035 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000500 AC: 12AN: 239998Hom.: 0 AF XY: 0.0000457 AC XY: 6AN XY: 131256
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GnomAD4 exome AF: 0.0000757 AC: 110AN: 1452814Hom.: 0 Cov.: 35 AF XY: 0.0000816 AC XY: 59AN XY: 723184
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GnomAD4 genome AF: 0.0000525 AC: 8AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74464
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 12, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2017 | A variant of uncertain significance has been identified in the KCNQ2 gene. The c.1347 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1347 C>T variant is observed in 1/8434 (0.01%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.1347 C>T creates a cryptic donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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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