rs144926751

Variant names:

• chr20-49482010-C-A
• rs144926751
• NM_004975.4:c.471G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-49482010-C-A
• chr20-49482010-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004975.4(KCNB1):​c.471G>T​(p.Glu157Asp) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNB1 NM_004975.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.99
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 26

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12211922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNB1	NM_004975.4	c.471G>T	p.Glu157Asp	missense_variant	Exon 1 of 2	ENST00000371741.6	NP_004966.1
KCNB1	XM_011528799.3	c.471G>T	p.Glu157Asp	missense_variant	Exon 2 of 3		XP_011527101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNB1	ENST00000371741.6	c.471G>T	p.Glu157Asp	missense_variant	Exon 1 of 2	1	NM_004975.4	ENSP00000360806.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251442 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 26 Uncertain:1

Mar 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs144926751, ExAC 0.01%). This sequence change replaces glutamic acid with aspartic acid at codon 157 of the KCNB1 protein (p.Glu157Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant has not been reported in the literature in individuals with KCNB1-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Inborn genetic diseases Uncertain:1

Aug 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.471G>T (p.E157D) alteration is located in exon 1 (coding exon 1) of the KCNB1 gene. This alteration results from a G to T substitution at nucleotide position 471, causing the glutamic acid (E) at amino acid position 157 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.85	.;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.62	N;N
PhyloP100		2.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.40
Sift	Benign	0.37	T;.
Sift4G	Benign	0.35	T;T
Polyphen		0.0060	B;B
Vest4		0.18
MutPred		0.20		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.87
MPC		1.6
ClinPred		0.55	D
GERP RS		4.2
PromoterAI		0.048	Neutral
Varity_R		0.17
gMVP		0.81
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs144926751; hg19: chr20-48098547;