1-110603637-CGG-TAA

Variant names:

• chr1-110603637-CGG-TAA
• NM_004974.4:c.1144_1146delCCGinsTTA
• KCNA2 p.Pro382Leu

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_004974.4(KCNA2):​c.1144_1146delCCGinsTTA​(p.Pro382Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P382R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNA2 NM_004974.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 32

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_004974.4
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004974.4. 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
	KCNA2	NM_004974.4	MANE Select	c.1144_1146delCCGinsTTA	p.Pro382Leu	missense	N/A	NP_004965.1	P16389-1
	KCNA2	NM_001204269.2		c.894+250_894+252delCCGinsTTA		intron	N/A	NP_001191198.1	P16389-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNA2	ENST00000316361.10	TSL:2 MANE Select	c.1144_1146delCCGinsTTA	p.Pro382Leu	missense	N/A	ENSP00000314520.4	P16389-1
	KCNA2	ENST00000369770.7	TSL:1	c.894+250_894+252delCCGinsTTA		intron	N/A	ENSP00000358785.3	P16389-2
	KCNA2	ENST00000485317.6	TSL:5	c.1144_1146delCCGinsTTA	p.Pro382Leu	missense	N/A	ENSP00000433109.1	P16389-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-111146259;