rs771845478
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP7BS1_SupportingBS2
The NM_172107.4(KCNQ2):c.1347C>T(p.Gly449Gly) 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
NM_172107.4 synonymous
NM_172107.4 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 -10 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP7
Synonymous conserved (PhyloP=-0.698 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000757 (110/1452814) while in subpopulation EAS AF= 0.000202 (8/39696). AF 95% confidence interval is 0.0000993. There are 0 homozygotes in gnomad4_exome. There are 59 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Ensembl
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 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 12, 2018 | - - |
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 | Dec 16, 2024 | - - |
Computational scores
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Name
Calibrated prediction
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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