rs1555889130

chr20-49374644-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004975.4(KCNB1):c.916C>T(p.Arg306Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R306H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 2.70

Genes affected

KCNB1 (HGNC:6231): (potassium voltage-gated channel subfamily B member 1) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shab-related subfamily. This member is a delayed rectifier potassium channel and its activity is modulated by some other family members. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_004975.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-49374643-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 982573.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, KCNB1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 20-49374644-G-A is Pathogenic according to our data. Variant chr20-49374644-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 449693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-49374644-G-A is described in UniProt as null. Variant chr20-49374644-G-A is described in Lovd as [Pathogenic]. Variant chr20-49374644-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNB1	NM_004975.4	c.916C>T	p.Arg306Cys	missense_variant	2/2	ENST00000371741.6
LOC105372649	XR_001754659.2	n.1201+42620G>A		intron_variant, non_coding_transcript_variant
KCNB1	XM_011528799.3	c.916C>T	p.Arg306Cys	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNB1	ENST00000371741.6	c.916C>T	p.Arg306Cys	missense_variant	2/2	1	NM_004975.4	P1
KCNB1	ENST00000635465.1	c.916C>T	p.Arg306Cys	missense_variant	3/3	1		P1
	ENST00000637341.1	n.206+42620G>A		intron_variant, non_coding_transcript_variant		5
KCNB1	ENST00000635878.1	c.97-75261C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 26 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 22, 2022	_x000D_ Criteria applied: PS2, PS4, PM1_SUP, PM2_SUP, PP2, PP3 -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 26 (MIM#616056). However, the ultimate result of each mechanism is channel dysfunction (PMID: 31512327). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a cluster of pathogenic variants, S4 of the voltage-sensing domain (PMID: 26477325). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The alternative change to a histidine has been reported once as likely pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent de novo variant in individuals with developmental and epileptic encephalopathy (ClinVar, PMID: 26477325, 29264397, 28806457, 31513310). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using transfected Neuro2a cells showed that the variant disrupts sensitivity and cooperativity of the sensor (PMID: 26477325). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 07, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNB1 function (PMID: 26477325). 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) performed at Invitae indicates that this missense variant is expected to disrupt KCNB1 protein function. ClinVar contains an entry for this variant (Variation ID: 449693). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 26477325, 28806457, 29264397). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 306 of the KCNB1 protein (p.Arg306Cys). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 15, 2021	The de novo c.916C>T (p.Arg306Cys variant in exon 2 of 2 of KCNB1 has been reported in multiple affected individuals in the available literature [PMID: 26477325.; PMID: 27652284; PMID: 29264397; PMID: 31513310; PMID: 32469098]. It is also submitted multiple times in ClinVar database by independent clinical laboratories and classified as Pathogenic/Likely Pathogenic (VarID: 449693). This variant is absent in gnomAD suggesting it is not a common benign variant in the populations represented in this database. In silico predictors suggest this variant is Pathogenic (REVEL; score: 0.86) and damaging (SIFT; score: 0). Functional studies have shown this variant in the voltage sensor domain S4, disrupts sensitivity and cooperativity of the sensor and results in loss of voltage sensing [2]. Given this evidence the de novo c.916C>T (p.Arg306Cys) variant identified in the KCNB1 gene is classified as Pathogenic. -

not provided Pathogenic:1 Other:1

not provided, no classification provided	in vitro	Kearney Laboratory, Northwestern University Feinberg School of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2022	Published functional studies demonstrate a damaging effect due to exhibiting higher resting membrane potentials, higher thresholds for action potential firing, and dramatically reduced ability of repetitive firing (Saitsu et al., 2015); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29264397, 31600826, 32581362, 32954514, 32725632, 26477325, 31513310, 32469098) -

Myoclonic absence seizure Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 03, 2020

The variant c.916C>T, p.(Arg306Cys) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was not maternal.The variant likely explains the NDD in this individual. -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.7	D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.91		Loss of MoRF binding (P = 0.0349);Loss of MoRF binding (P = 0.0349);
MVP		1.0
MPC		3.8
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.88
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555889130; hg19: chr20-47991181; COSMIC: COSV65569863; COSMIC: COSV65569863;