rs1553181280

Positions:

• chr1-110603663-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004974.4(KCNA2):​c.1120A>G​(p.Thr374Ala) 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: KCNA2 NM_004974.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 1-110603663-T-C is Pathogenic according to our data. Variant chr1-110603663-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 559647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-110603663-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.1120A>G	p.Thr374Ala	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	c.1120A>G	p.Thr374Ala	missense_variant	3/3	2	NM_004974.4	ENSP00000314520	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 32 Pathogenic:5

Pathogenic, criteria provided, single submitter	research	National Institute of Neuroscience, National Center of Neurology and Psychiatry	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 29050392). 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 KCNA2 protein function. ClinVar contains an entry for this variant (Variation ID: 559647). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 27117551, 29050392). 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 alanine, which is neutral and non-polar, at codon 374 of the KCNA2 protein (p.Thr374Ala). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Apr 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense c.1120A>G(p.Thr374Ala) variant in KCNA2 gene has been reported previously in heterozygous state in individual(s) affected with epileptic encephalopathies (Masnada et al., 2017). Experimental studies have shown that this missense change affects KCNA2 function (Masnada et al., 2017). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Thr at position 374 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr374Ala in KCNA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 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	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;D;D;D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D;.;.;.;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.9	H;.;.;H;H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.4	.;.;.;.;D;.;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;.;.;D;.;D;.
Sift4G	Pathogenic	0.0010	D;.;.;.;D;.;D;.
Polyphen		0.99	D;.;.;D;D;D;D;.
Vest4		0.93
MutPred		0.87		Loss of glycosylation at T374 (P = 0.0422);.;.;Loss of glycosylation at T374 (P = 0.0422);Loss of glycosylation at T374 (P = 0.0422);Loss of glycosylation at T374 (P = 0.0422);Loss of glycosylation at T374 (P = 0.0422);.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.82
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: rs1553181280; hg19: chr1-111146285; COSMIC: COSV60369449;