chr1-110603942-C-T

Position:

chr1-110603942-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_004974.4(KCNA2):c.841G>A(p.Ala281Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KCNA2
NM_004974.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.68

Variant links:

Genes affected

KCNA2 (HGNC:6220): (potassium voltage-gated channel subfamily A member 2) Potassium 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, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1. [provided by RefSeq, Jul 2008]

KCNA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNA2. . Gene score misZ 3.831 (greater than the threshold 3.09). Trascript score misZ 5.1665 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 32.

BP4

Computational evidence support a benign effect (MetaRNN=0.17719725).

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA2	NM_004974.4 linkuse as main transcript	c.841G>A	p.Ala281Thr	missense_variant	3/3	ENST00000316361.10	NP_004965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000316361.10 linkuse as main transcript	c.841G>A	p.Ala281Thr	missense_variant	3/3	2	NM_004974.4	ENSP00000314520	P1	P16389-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251388

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 32

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the KCNA2 protein (p.Ala281Thr). This variant is present in population databases (rs753926939, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with KCNA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 581469). 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 not expected to disrupt KCNA2 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Uncertain

0.59

D;.;.;.;.;.;D;D;D;D;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

.;T;D;T;T;T;.;.;.;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.033

MutationAssessor

Benign

0.035

N;N;.;.;.;.;N;N;N;N;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.17

.;N;.;.;.;.;.;N;.;N;.

REVEL

Uncertain

0.30

Sift

Benign

0.47

.;T;.;.;.;.;.;T;.;T;.

Sift4G

Benign

0.58

T;T;.;.;.;.;.;T;.;T;.

Polyphen

0.0

B;.;.;.;.;.;B;B;B;B;.

Vest4

0.075

MutPred

0.35

Gain of methylation at K277 (P = 0.0547);Gain of methylation at K277 (P = 0.0547);.;.;.;.;Gain of methylation at K277 (P = 0.0547);Gain of methylation at K277 (P = 0.0547);Gain of methylation at K277 (P = 0.0547);Gain of methylation at K277 (P = 0.0547);.;

MVP

0.61

MPC

1.1

ClinPred

0.096

GERP RS

5.9

Varity_R

0.11

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over