rs2100949783

Variant names:

• chr1-110673447-T-C
• rs2100949783
• NM_002232.5:c.1363A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PP2 PP5_Moderate BP4

The NM_002232.5(KCNA3):​c.1363A>G​(p.Ile455Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I455T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNA3 NM_002232.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.27
• Publications: 0 publications found

Genes affected

KCNA3 (HGNC:6221): (potassium voltage-gated channel subfamily A member 3) 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. It plays an essential role in T-cell proliferation and activation. This gene appears to be intronless and it is clustered together with KCNA2 and KCNA10 genes on chromosome 1. [provided by RefSeq, Jul 2008]

ENSG00000300042 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.0156 (below the threshold of 3.09). Trascript score misZ: 2.8395 (below the threshold of 3.09).
• PP5: Variant 1-110673447-T-C is Pathogenic according to our data. Variant chr1-110673447-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1334594.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26424646). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002232.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA3	NM_002232.5	MANE Select	c.1363A>G	p.Ile455Val	missense	Exon 1 of 1	NP_002223.3
	KCNA3	NR_109845.2		n.8A>G		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA3	ENST00000369769.4	TSL:6 MANE Select	c.1363A>G	p.Ile455Val	missense	Exon 1 of 1	ENSP00000358784.2	P22001-1
	KCNA3	ENST00000685980.2		n.1363A>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000513296.1	P22001-1
	KCNA3	ENST00000697409.1		n.1363A>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000513297.1	P22001-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	KCNA3-associated developmental and epileptic encephalopathy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Benign	0.65
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	-0.055	N
PhyloP100		6.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.10	N
REVEL	Uncertain	0.43
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0040	B
Vest4		0.42
MutPred		0.43		Loss of helix (P = 0.079)
MVP		0.75
ClinPred		0.40	T
GERP RS		5.9
Varity_R		0.12
gMVP		0.82
Mutation Taster		=90/10	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: rs2100949783; hg19: chr1-111216069;