rs1555889127
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_004975.4(KCNB1):c.935G>A(p.Arg312His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004975.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNB1 | NM_004975.4 | c.935G>A | p.Arg312His | missense_variant | 2/2 | ENST00000371741.6 | |
LOC105372649 | XR_001754659.2 | n.1201+42601C>T | intron_variant, non_coding_transcript_variant | ||||
KCNB1 | XM_011528799.3 | c.935G>A | p.Arg312His | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNB1 | ENST00000371741.6 | c.935G>A | p.Arg312His | missense_variant | 2/2 | 1 | NM_004975.4 | P1 | |
KCNB1 | ENST00000635465.1 | c.935G>A | p.Arg312His | missense_variant | 3/3 | 1 | P1 | ||
ENST00000637341.1 | n.206+42601C>T | intron_variant, non_coding_transcript_variant | 5 | ||||||
KCNB1 | ENST00000635878.1 | c.97-75242G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461868Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727232
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4Other:1
not provided, no classification provided | in vitro | Kearney Laboratory, Northwestern University Feinberg School of Medicine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Mar 14, 2022 | PM1, PS1, PM5, PP2, PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2020 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32954514, 31600826, 31513310, 28488083, 27928161, 28806457, 27652284) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | KCNB1: PS2:Very Strong, PM2, PP2, PP3, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Aug 09, 2019 | - - |
Developmental and epileptic encephalopathy, 26 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 312 of the KCNB1 protein (p.Arg312His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with developmental and epileptic encephalopathy (PMID: 31600826, 32954514). ClinVar contains an entry for this variant (Variation ID: 523478). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNB1 protein function. Experimental studies have shown that this missense change affects KCNB1 function (PMID: 31600826). This variant disrupts the p.Arg312 amino acid residue in KCNB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 27, 2022 | This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS3, PS4, PM1, PM5, PM2_SUP, PP2, PP3 - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Laboratoire de Génétique Moléculaire Institut de Recherche Necker Enfants Malades, CHU Paris - Hôpital Necker-Enfants Malades | Dec 01, 2019 | - - |
Epileptic encephalopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire Institut de Recherche Necker Enfants Malades, CHU Paris - Hôpital Necker-Enfants Malades | Mar 01, 2019 | - - |
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Apr 20, 2020 | - - |
Seizure;C0311394:Difficulty walking;C0454644:Delayed speech and language development;C0543888:Epileptic encephalopathy;C1858120:Generalized hypotonia;C3714756:Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
developmental encephalopathy with epilepsy Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Laboratoire de Génétique Moléculaire Institut de Recherche Necker Enfants Malades, CHU Paris - Hôpital Necker-Enfants Malades | Dec 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at