20-49374931-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_004975.4(KCNB1):​c.629C>A​(p.Thr210Lys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

KCNB1
NM_004975.4 missense

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 10.0
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the KCNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 76 curated pathogenic missense variants (we use a threshold of 10). The gene has 110 curated benign missense variants. Gene score misZ: 4.269 (above the threshold of 3.09). Trascript score misZ: 5.3923 (above the threshold of 3.09). GenCC associations: The gene is linked to undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 26.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.953
PP5
Variant 20-49374931-G-T is Pathogenic according to our data. Variant chr20-49374931-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1457665.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNB1NM_004975.4 linkc.629C>A p.Thr210Lys missense_variant Exon 2 of 2 ENST00000371741.6 NP_004966.1 Q14721
KCNB1XM_011528799.3 linkc.629C>A p.Thr210Lys missense_variant Exon 3 of 3 XP_011527101.1 Q14721
LOC105372649XR_001754659.2 linkn.1201+42907G>T intron_variant Intron 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNB1ENST00000371741.6 linkc.629C>A p.Thr210Lys missense_variant Exon 2 of 2 1 NM_004975.4 ENSP00000360806.3 Q14721

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 26 Pathogenic:1
Jul 13, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Other:1
-
Kearney Laboratory, Northwestern University Feinberg School of Medicine
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
33
DANN
Uncertain
0.99
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
0.71
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H;H
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.6
D;.
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;D
Vest4
0.84
MutPred
0.77
Gain of ubiquitination at T210 (P = 0.0238);Gain of ubiquitination at T210 (P = 0.0238);
MVP
0.99
MPC
3.4
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.97
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-47991468; API