chr20-49374931-G-A

Position:

• chr20-49374931-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2 PP3_Strong PP5_Very_Strong

The NM_004975.4(KCNB1):​c.629C>T​(p.Thr210Met) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 10.0

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]

KCNB1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNB1. . Gene score misZ 4.269 (greater than the threshold 3.09). Trascript score misZ 5.3923 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 26.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 20-49374931-G-A is Pathogenic according to our data. Variant chr20-49374931-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 542057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.629C>T	p.Thr210Met	missense_variant	2/2	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.629C>T	p.Thr210Met	missense_variant	3/3		XP_011527101.1
LOC105372649	XR_001754659.2	n.1201+42907G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.629C>T	p.Thr210Met	missense_variant	2/2	1	NM_004975.4	ENSP00000360806.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152186 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456110 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 26 Pathogenic:7

Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 15, 2018	The heterozygous p.Thr210Met variant in KCNB1 was identified by our study in one individual with epileptic encephalopathy. Trio exome analysis showed this variant to be de novo in our patient. This variant has also been identified in the literature as de novo in an 8-year old female with epileptic encephalopathy (Marini et al. 2017, PMID: 29264397). Additionally, it was identified in one other case with no additional data (Baldridge et al. 2017, PMID: 28252636). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2023	This variant disrupts the p.T210 amino acid residue in KCNB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28806457). 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. 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: 542057). This missense change has been observed in individual(s) with KCNB1-related disease (PMID: 29264397; Invitae). 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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 210 of the KCNB1 protein (p.Thr210Met). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 11, 2019	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 29, 2017	- -
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 threonine to methionine. (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 hotspot region or cluster of pathogenic variants in the ion transport protein domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed as de novo in multiple unrelated individuals with developmental and epileptic encephalopathy 26 (MIM#616056) (ClinVar, PMID: 33951346, PMID: 29264397). (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	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a de novo change in patients with developmental and epileptic encephalopathy (PMID: 28806457; 29264397). The KCNB1 gene is constrained against variation (Z-score= 4.27 and pLI = 1), and missense variants are a common mechanism of disease (HGMD, ClinVar database). The c.629C>T (p.Thr210Met) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.629C>T (p.Thr210Met) variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Aug 03, 2023	This variant has been identified by standard clinical testing. Selected ACMG criteria: Likely pathogenic (II):PP5;PP3;PP2;PM2;PS2 -

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	Dec 30, 2021	Reported in a child with unspecified developmental delay and no history of seizures (de Kovel et al., 2017); Published functional studies demonstrate a damaging effect as T210M alters protein expression (Kearney et al., 2015); 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: 31600826, 28806457, 29264397, 31513310, 32954514, 33951346) -

KCNB1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Feb 01, 2018

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.629C>T (p.T210M) alteration is located in exon 2 (coding exon 2) of the KCNB1 gene. This alteration results from a C to T substitution at nucleotide position 629, causing the threonine (T) at amino acid position 210 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported de novo in multiple individuals with features consistent with KCNB1-related developmental and epileptic encephalopathy (de Kovel, 2017; Marini, 2017; Bar 2020; Liu, 2021). Two other reportedly de novo alterations at the same codon, c.629C>G (p.Thr210Arg) and c.629C>A (p.Thr210Lys), have been detected in individuals with developmental delay, language delays, and epilepsy/seizures (Bar, 2020; de Kovel, 2017). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies suggest this variant results in a loss of K+ conductance and cell-surface KV2.1 expression, and that the substitution of a methionine would be incompatible with channel function of the S-1 pore interface; however, additional evidence is needed to confirm this finding (Kang, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

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	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.81		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.99
MPC		3.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.90
gMVP		0.96

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: rs1555889162; hg19: chr20-47991468;