1-110601794-ATGTGTGTGTGTGTGTGTGTGTG-ATGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr1-110601794-A-ATGTGTGTG
• rs35728918
• NM_004974.4:c.*1481_*1488dupCACACACA

Variant summary

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

The NM_004974.4(KCNA2):​c.*1481_*1488dupCACACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000028 (0 hom.)
• 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: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1481_*1488dupCACACACA		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.*1481_*1488dupCACACACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.0000736 AC: 10 AN: 135930 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000223

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000308

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000284 AC: 20 AN: 704464 Hom.: 0 Cov.: 6 AF XY: 0.0000238 AC XY: 8 AN XY: 336640

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

African (AFR) AF: 0.000273 AC: 4 AN: 14642

American (AMR) AF: 0.00 AC: 0 AN: 5340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9262

East Asian (EAS) AF: 0.00 AC: 0 AN: 14390

South Asian (SAS) AF: 0.00 AC: 0 AN: 12662

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: 0.0000230 AC: 14 AN: 608540

Other (OTH) AF: 0.0000728 AC: 2 AN: 27460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000001), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000735 AC: 10 AN: 135978 Hom.: 0 Cov.: 0 AF XY: 0.0000611 AC XY: 4 AN XY: 65460

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

African (AFR) AF: 0.000204 AC: 7 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: 0.000224 AC: 1 AN: 4464

South Asian (SAS) AF: 0.00 AC: 0 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: 0.0000308 AC: 2 AN: 64854

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000334), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 69

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;