1-110601794-ATGTGTGTGTGTGTGTGTGTGTG-ATGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr1-110601794-A-ATGTGTGTGTGTG
• rs35728918
• NM_004974.4:c.*1477_*1488dupCACACACACACA

Variant summary

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

The NM_004974.4(KCNA2):​c.*1477_*1488dupCACACACACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, 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.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.335
• 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 0 ACMG points.

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.*1477_*1488dupCACACACACACA		3_prime_UTR	Exon 3 of 3	NP_004965.1	P16389-1
	KCNA2	NM_001204269.2		c.1035+224_1035+235dupCACACACACACA		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.*1477_*1488dupCACACACACACA		3_prime_UTR	Exon 3 of 3	ENSP00000314520.4	P16389-1
	KCNA2	ENST00000369770.7	TSL:1	c.1035+224_1035+235dupCACACACACACA		intron	N/A	ENSP00000358785.3	P16389-2
	KCNA2	ENST00000633222.1	TSL:5	c.*1477_*1488dupCACACACACACA		3_prime_UTR	Exon 3 of 3	ENSP00000487785.1	P16389-1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 135930 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000284 AC: 2 AN: 704498 Hom.: 0 Cov.: 6 AF XY: 0.00000594 AC XY: 2 AN XY: 336654

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 14646

American (AMR) AF: 0.000187 AC: 1 AN: 5340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9264

East Asian (EAS) AF: 0.0000695 AC: 1 AN: 14390

South Asian (SAS) AF: 0.00 AC: 0 AN: 12664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1894

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 608566

Other (OTH) AF: 0.00 AC: 0 AN: 27460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 135930 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65390

African (AFR) AF: 0.00 AC: 0 AN: 34308

American (AMR) AF: 0.00 AC: 0 AN: 13446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3330

East Asian (EAS) AF: 0.00 AC: 0 AN: 4478

South Asian (SAS) AF: 0.00 AC: 0 AN: 4080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64864

Other (OTH) AF: 0.00 AC: 0 AN: 1878

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34

Splicing

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

Other links and lift over

dbSNP: rs35728918; hg19: chr1-111144416;