1-110601794-ATGTGTGTGTGTGTGTGTGTGTG-ATGTGTGTG

Variant names:

• chr1-110601794-ATGTGTGTGTGTGTG-A
• rs35728918
• NM_004974.4:c.*1475_*1488delCACACACACACACA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004974.4(KCNA2):​c.*1475_*1488delCACACACACACACA 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 DEL_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 0.00016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00028 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNA2 NM_004974.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.391
• 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: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1475_*1488delCACACACACACACA		3_prime_UTR_variant	Exon 3 of 3	ENST00000316361.10	NP_004965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000316361.10	c.*1475_*1488delCACACACACACACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.000162 AC: 22 AN: 135928 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: 0.000490

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000308

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000275 AC: 194 AN: 704484 Hom.: 1 AF XY: 0.000270 AC XY: 91 AN XY: 336644

African (AFR) AF: 0.0000683 AC: 1 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: 0.000765 AC: 11 AN: 14384

South Asian (SAS) AF: 0.000632 AC: 8 AN: 12664

European-Finnish (FIN) AF: 0.000195 AC: 2 AN: 10274

Middle Eastern (MID) AF: 0.000528 AC: 1 AN: 1894

European-Non Finnish (NFE) AF: 0.000276 AC: 168 AN: 608560

Other (OTH) AF: 0.0000728 AC: 2 AN: 27458

GnomAD4 genome AF: 0.000162 AC: 22 AN: 135976 Hom.: 0 Cov.: 0 AF XY: 0.000183 AC XY: 12 AN XY: 65458

African (AFR) AF: 0.00 AC: 0 AN: 34382

American (AMR) AF: 0.00 AC: 0 AN: 13460

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4464

South Asian (SAS) AF: 0.000491 AC: 2 AN: 4070

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000308 AC: 20 AN: 64852

Other (OTH) AF: 0.00 AC: 0 AN: 1892

Alfa AF: 0.00 Hom.: 69

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.39

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;