1-110601794-ATGTGTGTGTGTGTGTGTGTGTG-ATGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chr1-110601794-A-ATGTGTG
• rs35728918
• NM_004974.4:c.*1483_*1488dupCACACA

Variant summary

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

The NM_004974.4(KCNA2):​c.*1483_*1488dupCACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00050 (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: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

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

• BS2: High AC in GnomAd4 at 270 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.*1483_*1488dupCACACA		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.*1483_*1488dupCACACA		3_prime_UTR_variant	Exon 3 of 3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 268 AN: 135928 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00120

Gnomad EAS AF: 0.000447

Gnomad SAS AF: 0.000735

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000524

Gnomad OTH AF: 0.00160

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000497 AC: 350 AN: 704234 Hom.: 0 Cov.: 6 AF XY: 0.000481 AC XY: 162 AN XY: 336526

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

African (AFR) AF: 0.00301 AC: 44 AN: 14612

American (AMR) AF: 0.00112 AC: 6 AN: 5338

Ashkenazi Jewish (ASJ) AF: 0.000324 AC: 3 AN: 9262

East Asian (EAS) AF: 0.000208 AC: 3 AN: 14390

South Asian (SAS) AF: 0.000395 AC: 5 AN: 12660

European-Finnish (FIN) AF: 0.0000973 AC: 1 AN: 10274

Middle Eastern (MID) AF: 0.00158 AC: 3 AN: 1894

European-Non Finnish (NFE) AF: 0.000436 AC: 265 AN: 608364

Other (OTH) AF: 0.000729 AC: 20 AN: 27440

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00199 AC: 270 AN: 135976 Hom.: 1 Cov.: 0 AF XY: 0.00174 AC XY: 114 AN XY: 65458

African (AFR) AF: 0.00585 AC: 201 AN: 34380

American (AMR) AF: 0.00171 AC: 23 AN: 13460

Ashkenazi Jewish (ASJ) AF: 0.00120 AC: 4 AN: 3330

East Asian (EAS) AF: 0.000448 AC: 2 AN: 4464

South Asian (SAS) AF: 0.000737 AC: 3 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: 0.000524 AC: 34 AN: 64854

Other (OTH) AF: 0.00159 AC: 3 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		0.34

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;